seven-transmembrane G protein-coupled receptor superfamily; This hierarchical evolutionary model represents the seven-transmembrane (7TM) receptors, often referred to as G protein-coupled receptors (GPCRs), which transmit physiological signals from the outside of the cell to the inside via G proteins. GPCRs constitute the largest known superfamily of transmembrane receptors across the three kingdoms of life that respond to a wide variety of extracellular stimuli including peptides, lipids, neurotransmitters, amino acids, hormones, and sensory stimuli such as light, smell and taste. All GPCRs share a common structural architecture comprising of seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops. A general feature of GPCR signaling is agonist-induced conformational changes in the receptors, leading to activation of the heterotrimeric G proteins, which consist of the guanine nucleotide-binding G-alpha subunit and the dimeric G-beta-gamma subunits. The activated G proteins then bind to and activate numerous downstream effector proteins, which generate second messengers that mediate a broad range of cellular and physiological processes. However, some 7TM receptors, such as the type 1 microbial rhodopsins, do not activate G proteins. Based on sequence similarity, GPCRs can be divided into six major classes: class A (the rhodopsin-like family), class B (the Methuselah-like, adhesion and secretin-like receptor family), class C (the metabotropic glutamate receptor family), class D (the fungal mating pheromone receptors), class E (the cAMP receptor family), and class F (the frizzled/smoothened receptor family). Nearly 800 human GPCR genes have been identified and are involved essentially in all major physiological processes. Approximately 40% of clinically marketed drugs mediate their effects through modulation of GPCR function for the treatment of a variety of human diseases including bacterial infections.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530421724  83 AVAAVLLSRRTALSSTDTFLLHLAVADTLLVLTLPLWAVDAAVQWVFGSGLCKVAGALFNINFYAGALLLACISFDRYLN 162
Cdd:cd15180   20 LVLAVLLQKRRNLSVTDTFILHLALADILLLVTLPFWAVQAVHGWIFGTGLCKLAGAVFKINFYCGIFLLACISFDRYLS 99

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 530421724 163 IVHATQLYRRGPPARVTLTCLAVWGLCLLFALPDFIFLSAHHDERLNATHCQYNFPQ 219
Cdd:cd15180  100 IVHAVQMYSRKKPMLVHLSCLIVWLFCLLLSIPDFIFLEATKDPRQNKTECVHNFPQ 156

CXC chemokine receptor type 3, member of the class A family of seven-transmembrane G protein-coupled receptors; CXCR3 is an inflammatory chemotactic receptor for a group of CXC chemokines distinguished by the presence of the amino acid motif ELR immediately adjacent to their CXC motif. CXCR3 specifically binds three chemokines CXCL9 (monokine induced by gamma-interferon), CXCL10 (interferon induced protein of 10 kDa), and CXCL11 (interferon inducible T-cell alpha-chemoattractant, I-TAC). CXC3R is expressed on CD4+ Th1 and CD8+ cytotoxic T lymphocytes as well as highly on innate lymphocytes, such as NK cells and NK T cells, where it may mediate the recruitment of these cells to the sites of infection and inflammation. Chemokines are principal regulators for leukocyte trafficking, recruitment, and activation. Chemokine family membership is defined on the basis of sequence homology and on the presence of variations on a conserved cysteine motif, which allows the family to further divide into four subfamilies (CC, CXC, XC, and CX3C). Chemokines interact with seven-transmembrane receptors which are typically coupled to G protein for signaling. Currently, there are ten known receptors for CC chemokines, seven for CXC chemokines, and single receptors for the XC and CX3C chemokines.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530421724  83 AVAAVLLSRRTALSSTDTFLLHLAVADTLLVLTLPLWAVDAAVQWVFGSGLCKVAGALFNINFYAGALLLACISFDRYLN 162
Cdd:cd15180   20 LVLAVLLQKRRNLSVTDTFILHLALADILLLVTLPFWAVQAVHGWIFGTGLCKLAGAVFKINFYCGIFLLACISFDRYLS 99

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 530421724 163 IVHATQLYRRGPPARVTLTCLAVWGLCLLFALPDFIFLSAHHDERLNATHCQYNFPQ 219
Cdd:cd15180  100 IVHAVQMYSRKKPMLVHLSCLIVWLFCLLLSIPDFIFLEATKDPRQNKTECVHNFPQ 156

G protein-coupled chemokine receptor-like protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530421724  84 VAAVLLSRRTALSSTDTFLLHLAVADTLLVLTLPLWAVDA-AVQWVFGSGLCKVAGALFNINFYAGALLLACISFDRYLN 162
Cdd:PHA03087  60 IVIYVLTKTKIKTPMDIYLLNLAVSDLLFVMTLPFQIYYYiLFQWSFGEFACKIVSGLYYIGFYNSMNFITVMSVDRYIA 139

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 530421724 163 IVHATQLYRRGPPARVTLTCLAVWGLCLLFALPDFIFLSAHHDERLNATHCQYN 216
Cdd:PHA03087 140 IVHPVKSNKINTVKYGYIVSLVIWIISIIETTPILFVYTTKKDHETLICCMFYN 193

CXC chemokine receptor type 3, member of the class A family of seven-transmembrane G protein-coupled receptors; CXCR3 is an inflammatory chemotactic receptor for a group of CXC chemokines distinguished by the presence of the amino acid motif ELR immediately adjacent to their CXC motif. CXCR3 specifically binds three chemokines CXCL9 (monokine induced by gamma-interferon), CXCL10 (interferon induced protein of 10 kDa), and CXCL11 (interferon inducible T-cell alpha-chemoattractant, I-TAC). CXC3R is expressed on CD4+ Th1 and CD8+ cytotoxic T lymphocytes as well as highly on innate lymphocytes, such as NK cells and NK T cells, where it may mediate the recruitment of these cells to the sites of infection and inflammation. Chemokines are principal regulators for leukocyte trafficking, recruitment, and activation. Chemokine family membership is defined on the basis of sequence homology and on the presence of variations on a conserved cysteine motif, which allows the family to further divide into four subfamilies (CC, CXC, XC, and CX3C). Chemokines interact with seven-transmembrane receptors which are typically coupled to G protein for signaling. Currently, there are ten known receptors for CC chemokines, seven for CXC chemokines, and single receptors for the XC and CX3C chemokines.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530421724  83 AVAAVLLSRRTALSSTDTFLLHLAVADTLLVLTLPLWAVDAAVQWVFGSGLCKVAGALFNINFYAGALLLACISFDRYLN 162
Cdd:cd15180   20 LVLAVLLQKRRNLSVTDTFILHLALADILLLVTLPFWAVQAVHGWIFGTGLCKLAGAVFKINFYCGIFLLACISFDRYLS 99

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 530421724 163 IVHATQLYRRGPPARVTLTCLAVWGLCLLFALPDFIFLSAHHDERLNATHCQYNFPQ 219
Cdd:cd15180  100 IVHAVQMYSRKKPMLVHLSCLIVWLFCLLLSIPDFIFLEATKDPRQNKTECVHNFPQ 156

CXC chemokine receptor type 5, member of the class A family of seven-transmembrane G protein-coupled receptors; CXCR5 is a B-cell selective receptor that binds specifically to the homeostatic chemokine CXCL13 and regulates adaptive immunity. The receptor is found on all peripheral blood and tonsillar B cells and is involved in lymphocyte migration (homing) to specific tissues and development of normal lymphoid tissue. Chemokines are principal regulators for leukocyte trafficking, recruitment, and activation. Chemokine family membership is defined on the basis of sequence homology and on the presence of variations on a conserved cysteine motif, which allows the family to further divide into four subfamilies (CC, CXC, XC, and CX3C). Chemokines interact with seven-transmembrane receptors which are typically coupled to G protein for signaling. Currently, there are ten known receptors for CC chemokines, seven for CXC chemokines, and single receptors for the XC and CX3C chemokines.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530421724  84 VAAVLLSRRTALSSTDTFLLHLAVADTLLVLTLPLWAVDAAVQWVFGSGLCKVAGALFNINFYAGALLLACISFDRYLNI 163
Cdd:cd15181   21 VLTILLRRRRSRRTTENYLLHLALADLLLLLTFPFSVVESIAGWVFGTFLCKLVGAIHKLNFYCSSLLLACISVDRYLAI 100

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|..
gi 530421724 164 VHATQLYRRGPPARVTLTCLAVWGLCLLFALPDFIFLSAHHDERLNATHCQY 215
Cdd:cd15181  101 VHAIHSYRHRRLRSVHLTCGSIWLVCFLLSLPNLVFLEVETSTNANRTSCSF 152

CC chemokine receptor type 9, member of the class A family of seven-transmembrane G protein-coupled receptors; CCR9 is a homeostatic receptor specific for CCL25 (formerly known as thymus expressed chemokine) and is highly expressed on both immature and mature thymocytes as well as on intestinal homing T Lymphocytes and mucosal Lymphocytes. In cutaneous melanoma, activation of CCR9-CCL25 has been shown to stimulate metastasis to the small intestine. Chemokines are principal regulators for leukocyte trafficking, recruitment, and activation. Chemokine family membership is defined on the basis of sequence homology and on the presence of variations on a conserved cysteine motif, which allows the family to further divide into four subfamilies (CC, CXC, XC, and CX3C). Chemokines interact with seven-transmembrane receptors which are typically coupled to G protein for signaling. Currently, there are ten known receptors for CC chemokines, seven for CXC chemokines, and single receptors for the XC and CX3C chemokines. The CC chemokine receptors are all activating the G protein Gi.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530421724  84 VAAVLLSRRTALSSTDTFLLHLAVADTLLVLTLPLWAVDAAVQWVFGSGLCKVAGALFNINFYAGALLLACISFDRYLNI 163
Cdd:cd15174   21 VVLIYTYYRRRKTMTDVYLLNLAIADLLFLCTLPFWATAASSGWVFGTFLCKVVNSMYKINFYSCMLLLTCISVDRYIAI 100

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 530421724 164 VHAT--QLYRRGPPARVTLTCLAVWGLCLLFALPDFIFLSAHHDErlNATHCQYNFP 218
Cdd:cd15174  101 VQATkaHNSKNKRLLYSKLVCFFVWLLSTILSLPEILFSQSKEEE--SVTTCTMVYP 155

CC chemokine receptor type 6, member of the class A family of seven-transmembrane G protein-coupled receptors; CCR6 is the only known receptor identified for the chemokine CCL20 (also known as macrophage inflammatory protein-3alpha, MIP-3alpha). CCR6 is expressed by all mature human B cells, effector memory T-cells, and dendritic cells found in the gut mucosal immune system. CCL20 contributes to recruitment of CCR6-expressing cells to Peyer's patches and isolated lymphoid follicles in the intestine, thereby promoting the assembly and maintenance of organized lymphoid structures. Also, CCL20 expression is highly inducible in response to inflammatory signals. Thus, CCL20 is involved in both inflammatory and homeostatic functions in the immune system. Chemokines are principal regulators for leukocyte trafficking, recruitment, and activation. Chemokine family membership is defined on the basis of sequence homology and on the presence of variations on a conserved cysteine motif, which allows the family to further divide into four subfamilies (CC, CXC, XC, and CX3C). Chemokines interact with seven-transmembrane receptors which are typically coupled to G protein for signaling. Currently, there are ten known receptors for CC chemokines, seven for CXC chemokines, and single receptors for the XC and CX3C chemokines. The CC chemokine receptors are all activating the G protein Gi.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530421724  96 SSTDTFLLHLAVADTLLVLTLPLWAVDAAVQWVFGSGLCKVAGALFNINFYAGALLLACISFDRYLNIVHATQLYR-RGP 174
Cdd:cd15172   33 SMTDVYLLNMAIADILFVLTLPFWAVYEAHQWIFGNFSCKLLRGIYAINFYSGMLLLACISVDRYIAIVQATKSFRlRSR 112

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 530421724 175 P-ARVTLTCLAVWGLCLLFALPDFIFLSAHHDERLNATHCQYNFP 218
Cdd:cd15172  113 TlAYSKLICAAVWLLAILISLPTFIFSEVYDFGLEEQYVCEPKYP 157

CXC chemokine receptor type 4, member of the class A family of seven-transmembrane G protein-coupled receptors; CXCR4 is the only known G protein-coupled chemokine receptor for the key homeostatic ligand CXCL12, which is constitutively secreted by bone marrow stromal cells. Atypical chemokine receptor CXCR7 (ACKR3) also binds CXCL12, but activates signaling in a G protein-independent manner. CXCR4 is also a co-receptor for HIV infection and plays critical roles in the development of immune system during both lymphopoiesis and myelopoiesis. Chemokines are principal regulators for leukocyte trafficking, recruitment, and activation. Chemokine family membership is defined on the basis of sequence homology and on the presence of variations on a conserved cysteine motif, which allows the family to further divide into four subfamilies (CC, CXC, XC, and CX3C). Chemokines interact with seven-transmembrane receptors which are typically coupled to G protein for signaling. Currently, there are ten known receptors for CC chemokines, seven for CXC chemokines, and single receptors for the XC and CX3C chemokines.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530421724  96 SSTDTFLLHLAVADTLLVLTLPLWAVDAAVQWVFGSGLCKVAGALFNINFYAGALLLACISFDRYLNIVHAT--QLYRRG 173
Cdd:cd15179   33 TMTDKYRLHLSVADLLFVLTLPFWAVDAAANWYFGNFLCKAVHVIYTVNLYSSVLILAFISLDRYLAIVHATnsQRPRKL 112

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 530421724 174 PPARVtlTCLAVWGLCLLFALPDFIFlsAHHDERLNATHCQYNFPQ 219
Cdd:cd15179  113 LAEKV--VYVGVWLPALLLTVPDLVF--AKVSELDDRYICDRIYPE 154

angiotesin receptor family and its related G protein-coupled receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; This group includes the angiotensin receptors, the bradykinin receptors, apelin receptor as well as putative G-protein coupled receptors (GPR15 and GPR25). Angiotensin II (Ang II), the main effector in the renin-angiotensin system, plays a crucial role in the regulation of cardiovascular homeostasis through its type 1 (AT1) and type 2 (AT2) receptors. Ang II contributes to cardiovascular diseases such as hypertension and atherosclerosis via AT1R activation. Ang II increases blood pressure through Gq-mediated activation of phospholipase C, resulting in phosphoinositide (PI) hydrolysis and increased intracellular calcium levels. Through the AT2 receptor, Ang II counteracts the vasoconstrictor action of AT1R and thereby induces vasodilation, sodium excretion, and reduction of blood pressure. Bradykinins (BK) are pro-inflammatory peptides that mediate various vascular and pain responses to tissue injury through its B1 and B2 receptors. Apelin (APJ) receptor binds the endogenous peptide ligands, apelin and Toddler/Elabela. APJ is an adipocyte-derived hormone that is ubiquitously expressed throughout the human body, and Toddler/Elabela is a short secretory peptide that is required for normal cardiac development in zebrafish. Activation of APJ receptor plays key roles in diverse physiological processes including vasoconstriction and vasodilation, cardiac muscle contractility, angiogenesis, and regulation of water balance and food intake. Orphan receptors, GPR15 and GPR25, share strong sequence homology to the angiotensin II type AT1 and AT2 receptors.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530421724  84 VAAVLLSRRTALSSTDTFLLHLAVADTLLVLTLPLWAVDAAVQ--WVFGSGLCKVAGALFNINFYAGALLLACISFDRYL 161
Cdd:cd14985   21 VVWVFLFPRGPKRVADIFIANLAAADLVFVLTLPLWATYTANQydWPFGAFLCKVSSYVISVNMFASIFLLTCMSVDRYL 100

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 530421724 162 NIVHATQLYRRGPPARVTLTCLAVWGLCLLFALPDFIFLSAHHDERLNATHCQYNFP 218
Cdd:cd14985  101 AIVHPVASRRLRRRRQARVTCALIWVVACLLSLPTFLLRSLQAIENLNKTACIMLYP 157

purinoceptor and its related proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; Members of this subfamily include lysophosphatidic acid receptor, P2 purinoceptor, protease-activated receptor, platelet-activating factor receptor, Epstein-Barr virus induced gene 2, proton-sensing G protein-coupled receptors, GPR35, and GPR55, among others. All GPCRs have a common structural architecture comprising of seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops. A general feature of GPCR signaling is agonist-induced conformational changes in the receptors, leading to activation of the heterotrimeric G proteins, which consist of the guanine nucleotide-binding G-alpha subunit and the dimeric G-beta-gamma subunits. The activated G proteins then bind to and activate numerous downstream effector proteins, which generate second messengers that mediate a broad range of cellular and physiological processes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530421724  87 VLLSRRTALSSTDTFLLHLAVADTLLVLTLPLWAVDAAVQ--WVFGSGLCKVAGALFNINFYAGALLLACISFDRYLNIV 164
Cdd:cd14982   24 VFLRKMKKRSPTTIYMINLALADLLFVLTLPFRIYYYLNGgwWPFGDFLCRLTGLLFYINMYGSILFLTCISVDRYLAVV 103

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*....
gi 530421724 165 HATQLYRRGPPARVTLTCLAVWGLCLLFALPdFIFLSAHHDERLNATHC 213
Cdd:cd14982  104 HPLKSRRLRRKRYAVGVCAGVWILVLVASVP-LLLLRSTIAKENNSTTC 151

CC chemokine receptor type 7, member of the class A family of seven-transmembrane G protein-coupled receptors; CCR7 is a major homeostatic receptor responsible for lymph node development and effective adaptive immune responses and plays a critical role in trafficking of dendritic cells and B and T lymphocytes. Its only two ligands, CCL and CCl21, are primarily produced by stromal cells in the T cell zones of lymph nodes and spleen. Chemokines are principal regulators for leukocyte trafficking, recruitment, and activation. Chemokine family membership is defined on the basis of sequence homology and on the presence of variations on a conserved cysteine motif, which allows the family to further divide into four subfamilies (CC, CXC, XC, and CX3C). Chemokines interact with seven-transmembrane receptors which are typically coupled to G protein for signaling. Currently, there are ten known receptors for CC chemokines, seven for CXC chemokines, and single receptors for the XC and CX3C chemokines. The CC chemokine receptors are all activating the G protein Gi.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530421724  98 TDTFLLHLAVADTLLVLTLPLWAVDAAVQWVFGSGLCKVAGALFNINFYAGALLLACISFDRYLNIVHATQLYRRGPPAR 177
Cdd:cd15175   35 TDIYLLNLALADILFLLTLPFWAASAAKKWVFGEEMCKAVYCLYKMSFFSGMLLLMCISIDRYFAIVQAASAHRHRSRAV 114

                         90       100
                 ....*....|....*....|....
gi 530421724 178 V--TLTCLAVWGLCLLFALPDFIF 199
Cdd:cd15175  115 FisKVSSLGVWVLAFILSIPELLY 138

G protein-coupled receptor 25, member of the class A family of seven-transmembrane G protein-coupled receptors; GPR25 is an orphan G-protein coupled receptor that shares strong sequence homology to GPR15 and the angiotensin II receptors. These closely related receptors form a group within the class A G-protein coupled receptors (GPCRs). GPR15 controls homing of T cells, especially FOXP3(+) regulatory T cells, to the large intestine mucosa and thereby mediates local immune homeostasis. Moreover, GRP15-deficient mice were shown to be prone to develop more severe large intestine inflammation. Angiotensin II (Ang II), the main effector in the renin-angiotensin system, plays a crucial role in the regulation of cardiovascular homeostasis through its type 1 (AT1) and type 2 (AT2) receptors.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530421724  84 VAAVLLSRRTALSSTDTFLLHLAVADTLLVLTLPLWAVDAAV--QWVFGSGLCKVAGALFNINFYAGALLLACISFDRYL 161
Cdd:cd15193   21 VIALMSKRSTTKRLVDTFVLNLAVADLVFVLTLPFWAASTALggQWLFGEGLCKLSSFIIAVNRCSSILFLTGMSVDRYL 100

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 530421724 162 NIVHATQLYRRGPPARVTLTCLAVWGLCLLFALPDFIF 199
Cdd:cd15193  101 AVVKLLDSRPLRTRRCALITCCIIWAVSLVLGIPSLVY 138

apelin receptor, member of the class A family of seven-transmembrane G protein-coupled receptors; Apelin (APJ) receptor is a G protein-coupled receptor that binds the endogenous peptide ligands, apelin and Toddler/Elabela. APJ is an adipocyte-derived hormone that is ubiquitously expressed throughout the human body and Toddler/Elabela is a short secretory peptide that is required for normal cardiac development in zebrafish. Activation of APJ receptor plays key roles in diverse physiological processes including vasoconstriction and vasodilation, cardiac muscle contractility, angiogenesis, and regulation of water balance and food intake.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530421724  87 VLLSRRTALSSTDTFLLHLAVADTLLVLTLPLWAVDAAV--QWVFGSGLCKVAGALFNINFYAGALLLACISFDRYLNIV 164
Cdd:cd15190   35 VFRSKRKRRRSADTFIANLALADLTFVVTLPLWAVYTALgyHWPFGSFLCKLSSYLVFVNMYASVFCLTGLSFDRYLAIV 114

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 530421724 165 HATQLYRRGPPARVTLTCLAVWGLCLLFALPDFIFLSAHHDERLNATHCQYNF 217
Cdd:cd15190  115 RSLASAKLRSRTSGIVALGVIWLLAALLALPALILRTTSDLEGTNKVICDMDY 167

XC chemokine receptor 1, member of the class A family of seven-transmembrane G protein-coupled receptors; XCR1 is a chemokine receptor specific for XCL1 and XCL2 (previously called lymphotactin alpha/beta), which differ in only two amino acids. XCL1/2 is the only member of the C chemokine subfamily, which is unique as containing only two of the four cysteines that are found in other chemokine families. Human XCL1/2 has been shown to be secreted by activated CD8+ T cells and upon activation of the innate immune system. Chemokines are principal regulators for leukocyte trafficking, recruitment, and activation. Chemokine family membership is defined on the basis of sequence homology and on the presence of variations on a conserved cysteine motif, which allows the family to further divide into four subfamilies (CC, CXC, XC, and CX3C). Chemokines interact with seven-transmembrane receptors which are typically coupled to G protein for signaling.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530421724  96 SSTDTFLLHLAVADTLLVLTLPLWAVDAAVQWVFGSGLCKVAGALFNINFYAGALLLACISFDRYLNIVHATQLYRRGPP 175
Cdd:cd15182   33 TLTNIFILNLAISDLLFTFTLPFWASYHSSGWIFGEILCKAVTSIFYIGFYSSILFLTLMTIDRYLAVVHPLSALRSRKL 112

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 530421724 176 ARVTLTCLAVWGLCLLFALPDFIFLSAHHDERLNAThCQY 215
Cdd:cd15182  113 RYASLVSVAVWVISILASLPELILSTVMKSDEDGSL-CEY 151

CC chemokine receptor types 5 and 2, member of the class A family of seven-transmembrane G protein-coupled receptors; CCR2 and CCR5 share very high amino acid sequence identity. Both receptors play important roles in the trafficking of monocytes/macrophages and are implicated in the pathogenesis of immunologic diseases (rheumatoid arthritis, celiac disease, and transplant rejection) and cardiovascular diseases (atherosclerosis and autoimmune hepatitis). CCR2 is a receptor specific for members of the monocyte chemotactic protein family, including CCL2, CCL7, and CCL13. Conversely, CCR5 is a major co-receptor for HIV infection and binds many CC chemokine ligands, including CC chemokine ligands including CCL2, CCL3, CCL4, CCL5, CCL11, CCL13, CCL14, and CCL16. CCR2 is expressed primarily on blood monocytes and memory T cells, whereas CCR5 is expressed on antigen-presenting cells (macrophages and dendritic cells) and activated T effector cells. Chemokines are principal regulators for leukocyte trafficking, recruitment, and activation. Chemokine family membership is defined on the basis of sequence homology and on the presence of variations on a conserved cysteine motif, which allows the family to further divide into four subfamilies (CC, CXC, XC, and CX3C). Chemokines interact with seven-transmembrane receptors which are typically coupled to G protein for signaling. Currently, there are ten known receptors for CC chemokines, seven for CXC chemokines, and single receptors for the XC and CX3C chemokines.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530421724  84 VAAVLLSRRTALSSTDTFLLHLAVADTLLVLTLPLWAVDAAVQWVFGSGLCKVAGALFNINFYAGALLLACISFDRYLNI 163
Cdd:cd15184   21 VVLILINCKKLKSMTDIYLLNLAISDLLFLLTLPFWAHYAANEWVFGNAMCKLLTGLYHIGFFSGIFFIILLTIDRYLAI 100

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 530421724 164 VHATQLYRRGPPARVTLTCLAVWGLCLLFALPDFIFLSAHHDErlNATHCQYNFPQ 219
Cdd:cd15184  101 VHAVFALKARTVTFGVVTSVVTWVVAVFASLPGIIFTKSQKEG--SHYTCSPHFPP 154

opioid receptors and related proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; This group includes opioid receptors, somatostatin receptors, melanin-concentrating hormone receptors (MCHRs), and neuropeptides B/W receptors. Together they constitute the opioid receptor-like family, members of the class A G-protein coupled receptors. Opioid receptors are coupled to inhibitory G proteins of the G(i/o) family and are involved in regulating a variety of physiological functions such as pain, addiction, mood, stress, epileptic seizure, and obesity, among many others. G protein-coupled somatostatin receptors (SSTRs), which display strong sequence similarity with opioid receptors, binds somatostatin (somatotropin release inhibiting factor), a polypeptide hormone that regulates a wide variety of physiological functions such as neurotransmission, cell proliferation, contractility of smooth muscle cells, and endocrine signaling as well as inhibition of the release of many secondary hormones. MCHR binds melanin concentrating hormone and is presumably involved in the neuronal regulation of food intake. Despite strong homology with somatostatin receptors, MCHR does not appear to bind somatostatin. Neuropeptides B/W receptors are primarily expressed in the CNS and stimulate the cortisol secretion by activating the adenylate cyclase- and the phospholipase C-dependent signaling pathways.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530421724  98 TDTFLLHLAVADTLLVLTLPLWAVDAAVQ-WVFGSGLCKVAGALFNINFYAGALLLACISFDRYLNIVHATQLYRRGPPA 176
Cdd:cd14970   35 TNIYILNLAVADELFLLGLPFLATSYLLGyWPFGEVMCKIVLSVDAYNMFTSIFCLTVMSVDRYLAVVHPVKSLRFRTPR 114

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|..
gi 530421724 177 RVTLTCLAVWGLCLLFALPDFIFLSAHHDErLNATHCQYNFP 218
Cdd:cd14970  115 KAKLVSLCVWALSLVLGLPVIIFARTLQEE-GGTISCNLQWP 155

CC chemokine receptor type 8, member of the class A family of seven-transmembrane G protein-coupled receptors; CCR8, the receptor for the CC chemokines CCL1 and CC16, is highly expressed on allergen-specific T-helper type 2 cells, and is implicated in the pathogenesis of human asthma. CCL1- and CCR8-expressing CD4+ effector T lymphocytes are shown to have a critical role in lung mucosal inflammatory responses. CCR8 is also a functional receptor for CCL16, a liver-expressed CC chemokine that involved in attracting lymphocytes, dendritic cells, and monocytes. Chemokines are principal regulators for leukocyte trafficking, recruitment, and activation. Chemokine family membership is defined on the basis of sequence homology and on the presence of variations on a conserved cysteine motif, which allows the family to further divide into four subfamilies (CC, CXC, XC, and CX3C). Chemokines interact with seven-transmembrane receptors which are typically coupled to G protein for signaling. Currently, there are ten known receptors for CC chemokines, seven for CXC chemokines, and single receptors for the XC and CX3C chemokines.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530421724  84 VAAVLLSRRTALSSTDTFLLHLAVADTLLVLTLPLWAVDAAVQWVFGSGLCKVAGALFNINFYAGALLLACISFDRYLNI 163
Cdd:cd15187   21 VIWVLVACKKLRSMTDVYLLNLAASDLLFVFSLPFQAYYLLDQWVFGNAMCKIVSGAYYIGFYSSMFFITLMSIDRYLAI 100

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 530421724 164 VHATQLYRRGPPARVTLTCLAVWGLCLLFALPDFIFLSAHHDErlNATHCQYNFPQ 219
Cdd:cd15187  101 VHAVYALKVRTASHGTILSLALWLVAILASVPLLVFYQVASED--GRLQCIPFYPG 154

CXC chemokine receptor 7, member of the class A family of seven-transmembrane G protein-coupled receptors; ACKR3, also known as CXCR7, is an atypical chemokine receptor for CXCL12 and CXCR11. Unlike the classical chemokine receptors, ACKR3 contains a DRYLSIT-sequence instead of the conserved DRYLAIV motif in the second intracellular loop, which is required for G-protein coupling. Thus, ACKR3 does not activate classical GPCR signaling, instead induces beta-arrestin recruitment which is leading to ligand internalization and MAP-kinase activation. It is acting as a scavenger for CXCL12 and, to a lesser degree, for CXCL11. ACKR3 is highly expressed by blood vascular endothelial cells in brain, in numerous embryonic and neonatal tissues, in inflamed tissues and in a variety of cancers such as lymphomas, sarcomas, prostate and breast cancers, and gliomas. Five receptors have been identified for the ACKR family, including CC-Chemokine Receptors like 1 and 2 (CCRL1 and CCRL2), CXCR7, DARC, and D6. Both ACKR1 (DARC) and ACKR3 (CXCR7) show low sequence homology to the classic chemokine receptors.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530421724  98 TDTFLLHLAVADTLLVLTLPLWAVDAAV--QWVFGSGLCKVAGALFNINFYAGALLLACISFDRYLNIVHATQLYRRGPP 175
Cdd:cd14987   35 THLYILNLAIADLCVVATLPVWVVSLVQhnQWPMGEFTCKITHLIFSINLFGSIFFLTCMSVDRYLSVTLFGNTSSRRKK 114

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 530421724 176 ARVTLTCLAVWGLCLLFALPDFIFLSAHHDERLNATHCQYNFPQ 219
Cdd:cd14987  115 IVRRIICVLVWLLAFVASLPDTYFLKTVTSPSNNETYCRSFYPE 158

lysophosphatidic acid receptor 6, member of the class A family of seven-transmembrane G protein-coupled receptors; Lysophosphatidic acid receptor 6 (LPAR6), also known as P2Y5, is a G(i), G(12/13) G protein-coupled receptor that is activated by the bioactive lipid lysophosphatidic acid (LPA), which is released by activated platelets and constitutively present in serum. LPAR6 plays an important role in maintenance of human hair growth. Thus, mutations in the receptor are responsible for both autosomal recessive wooly hair and hypotrichosis. Phylogenetic analysis of the class A GPCRs shows that LAPR6 (P2Y5) is classified into the cluster consisting of receptors that are preferentially activated by adenosine and uridine nucleotides. Although LPA6 (P2Y5) is expressed in human hair follicle cells, LPA4 and LPA5 are not. These three receptors are highly homologous and mediate an increase in intracellular cAMP production.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530421724  98 TDTFLLHLAVADTLLVLTLPLWAVDAAVQ-WVFGSGLCKVAGALFNINFYAGALLLACISFDRYLNIVHATQLYRRGPPA 176
Cdd:cd15156   35 TTTYMINLAISDLLFVFTLPFRIFYFVQRnWPFGDLLCKISVTLFYTNMYGSILFLTCISVDRFLAIVYPFRSKTLRTKR 114

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 530421724 177 RVTLTCLAVWGLCLLFALPDFIFLSAHHDERLNATHCQYNFPQ 219
Cdd:cd15156  115 NAKIVCAAVWLTVLAGSLPASFFQSTNNQLNNNSETCFENFSS 157

CX3C chemokine receptor 1, member of the class A family of seven-transmembrane G protein-coupled receptors; CX3CR1 is an inflammatory receptor specific for CX3CL1 (also known as fractalkine in human), which is involved in the adhesion and migration of leukocytes. The CX3C chemokine subfamily is only represented by CX3CL1, which exists in both soluble and membrane-anchored forms. Membrane-anchored form promotes strong adhesion of receptor-bearing leukocytes to CX3CL1-expressing endothelial cells. On the other hand, soluble CX3CL1, which is released by the proteolytic cleavage of membrane-anchored CX3CL1, is a potent chemoattractant for CX3CR1-expressing T cells and monocytes. Chemokine family membership is defined on the basis of sequence homology and on the presence of variations on a conserved cysteine motif, which allows the family to further divide into four subfamilies (CC, CXC, XC, and CX3C). Chemokines interact with seven-transmembrane receptors which are typically coupled to G protein for signaling.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530421724  84 VAAVLLSRRTALSSTDTFLLHLAVADTLLVLTLPLWAVDAAVQWVFGSGLCKVAGALFNINFYAGALLLACISFDRYLNI 163
Cdd:cd15186   21 VVLALTNSGKSKSITDIYLLNLALSDLLFVATLPFWTHYLINEWGLHNAMCKLTTAFFFIGFFGGIFFITVISIDRYLAI 100

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 530421724 164 VHATQLYRRGPPARVTLTCLAVWGLCLLFALPDFIF 199
Cdd:cd15186  101 VLAANSMNNRTVQHGVTISLGVWAAAILVAVPQFMF 136

anaphylatoxin receptors and related G protein-coupled chemokine receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; This subfamily of G-protein coupled receptors includes anaphylatoxin receptors, formyl peptide receptors (FPR), prostaglandin D2 receptor 2, GPR1, and related chemokine receptors. The anaphylatoxin receptors are a group of G-protein coupled receptors that bind anaphylatoxins. The members of this group include C3a and C5a receptors. The formyl peptide receptors (FPRs) are chemoattractant GPCRs that involved in mediating immune responses to infection. They are expressed mainly on polymorphonuclear and mononuclear phagocytes and bind N-formyl-methionyl peptides (FMLP), which are derived from the mitochondrial proteins of ruptured host cells or invading pathogens. Chemokine receptor-like 1 (also known as chemerin receptor 23) is a GPCR for the chemoattractant adipokine chemerin, also known as retinoic acid receptor responder protein 2 (RARRES2), and for the omega-3 fatty acid derived molecule resolvin E1. Interaction with chemerin induces activation of the MAPK and PI3K signaling pathways leading to downstream functional effects, such as a decrease in immune responses, stimulation of adipogenesis, and angiogenesis. On the other hand, resolvin E1 negatively regulates the cytokine production in macrophages by reducing the activation of MAPK1/3 and NF-kB pathways. Prostaglandin D2 receptor, also known as CRTH2, is a chemoattractant G-protein coupled receptor expressed on T helper type 2 cells that binds prostaglandin D2 (PGD2). PGD2 functions as a mast cell-derived mediator to trigger asthmatic responses and also causes vasodilation. PGD2 exerts its inflammatory effects by binding to two G-protein coupled receptors, the D-type prostanoid receptor (DP) and PD2R2 (CRTH2). PD2R2 couples to the G protein G(i/o) type which leads to a reduction in intracellular cAMP levels and an increase in intracellular calcium. GPR1 is an orphan receptor that can be activated by the leukocyte chemoattractant chemerin, thereby suggesting that some of the anti-inflammatory actions of chemerin may be mediated through GPR1.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530421724  91 RRTAlssTDTFLLHLAVADTLLVLTLPLWAVDAAV--QWVFGSGLCKVAGALFNINFYAGALLLACISFDRYLNIVHA-- 166
Cdd:cd14974   30 KRTV---NTVWFLNLALADFLFCLFLPFLIVYIAMghHWPFGSVLCKLNSFVISLNMFASVFLLTAISLDRCLLVLHPvw 106

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 530421724 167 TQLYRRgpPARVTLTCLAVWGLCLLFALPDFIFLSAHHDER 207
Cdd:cd14974  107 AQNHRT--VRLASVVCVGIWILALVLSVPYFVFRDTVTHHN 145

G protein-coupled receptor 55 and similar proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; GPR55 shares closest homology with GPR35, and they belong to the class A G protein-coupled receptor superfamily, which all have a common structural architecture comprising of seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops. GPR55 has been reported to couple to G(13), G(12), or G(q) proteins. Activation of GPR55 leads to activation of phospholipase C, RhoA, ROCK, ERK, p38MAPK, and calcium release. Lysophosphatidylinositol (LPI) is currently considered as the endogenous ligand for GPR55, although the receptor was initially de-orphanized as a cannabinoid receptor and binds many cannabinoid ligands.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530421724  87 VLLSRRTALSSTDTFLLHLAVADTLLVLTLPLWAVDAAVQWVFGSGLCKVAGALFNINFYAGALLLACISFDRYLNIVHA 166
Cdd:cd15165   24 VFLFKIKKWTESTIYMINLALNDLLLLLSLPFKMHSSKKQWPLGRTLCSFLESLYFVNMYGSILIIVCISVDRYIAIRHP 103

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 530421724 167 TQLYRRGPPARVTLTCLAVWGLCLLFALPDFIFlsahHDERLNATHCQYNF 217
Cdd:cd15165  104 FLAKRLRSPRKAAIVCLTIWVFVWAGSIPIYSF----HDKPTNNTRCFHGF 150

proton-sensing G protein-coupled receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; Proton/pH-sensing G-protein coupled receptors sense pH of 7.6 to 6.0. They mediate a variety of biological activities in neutral and mildly acidic pH conditions, whereas the acid-sensing ionotropic ion channels typically sense strong acidic pH. The proton/pH-sensing receptor family includes the G2 accumulation receptor (G2A, also known as GPR132), the T cell death associated gene-8 (TDAG8, GPR65) receptor, ovarian cancer G-protein receptor 1 (OGR-1, GPR68), and G-protein-coupled receptor 4 (GPR4).

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530421724 101 FLLHLAVADTLLVLTLPLWAVDAAVQ--WVFGSGLCKVAGALFNINFYAGALLLACISFDRYLNIVHATQLYRRGPPARV 178
Cdd:cd15160   38 YLLNLSLSDLLYILTLPLWIDYTANHhnWTFGPLSCKVVGFFFYTNIYASIGFLCCIAVDRYLAVVHPLRFRGLRTRRFA 117

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 530421724 179 TLTCLAVWGLCLLFALPdFIFLSAHHDERLNATHCQYNFP 218
Cdd:cd15160  118 LKVSASIWVLELGTHSV-FLGHDELFRDEPNHTLCYEKYP 156

G protein-coupled receptor 17, member of the class A family of seven-transmembrane G protein-coupled receptors; GPR17 is a Forkhead box protein O1 (FOXO1) target and abundantly expressed in agouti-related peptide (AGRP) neurons. FOXO1 is a transcription factor that plays key roles in regulation of gluconeogenesis and glycogenolysis by insulin signaling. For instance, food intake and body weight increase when hypothalamic FOXO1 is activated, whereas they both decrease when FOXO1 is inhibited. However, a recent study has been reported that GPR17 deficiency in mice did not affect food intake or glucose homeostasis. Thus, GPR17 may not play a role in the control of food intake, body weight, or glycemic control. GPR17 is phylogenetically closely related to purinergic P2Y and cysteinyl-leukotriene receptors.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530421724  91 RRTALSSTDTFLLHLAVADTLLVLTLPLWAVD--AAVQWVFGSGLCKVAGALFNINFYAGALLLACISFDRYLNIVHATQ 168
Cdd:cd15161   28 DRKSGTPSNVFLMHLAVADLSYVLILPMRLVYhlSGNHWPFGEVPCRLAGFLFYLNMYASLYFLACISVDRFLAIVHPVK 107

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 530421724 169 LYRRGPPARVTLTCLAVWGLCLLFALPdfIFLSAHHDERLNATHC 213
Cdd:cd15161  108 SMKIRKPLYAHVVCGFLWVIVTVAMAP--LLVSPQTVEVNNTTVC 150

lysophosphatidic acid receptor 5, member of the class A family of seven-transmembrane G protein-coupled receptors; Lysophosphatidic acid receptor 5 (LPAR5) is a G protein-coupled receptor that binds the bioactive lipid lysophosphatidic acid (LPA) and is involved in maintenance of human hair growth. Phylogenetic analysis of the class A GPCRs shows that LAPR5 is classified into the cluster consisting receptors that are preferentially activated by adenosine and uridine nucleotides. Although LPA6 (P2Y5) is expressed in human hair follicle cells, LPA4 and LPA5 are not. These three receptors are highly homologous and mediate an increase in intracellular cAMP production. Activation of LPAR5 is coupled to G(q) and G(12/13) proteins.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530421724  95 LSSTDTFLLHLAVADTLLVLTLPLWAVDAAV-QWVFGSGLCKVAGALFNINFYAGALLLACISFDRYLNIVHATQLYRRG 173
Cdd:cd15154   32 HSVVSIYMCNLALSDLLFTLSLPLRIYYYANhYWPFGNFLCQFSGSIFQMNMYGSCLFLMCINVDRYLAIVHPLRFRHLR 111

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 530421724 174 PPARVTLTCLAVWGLCLLFALPDFIflsAHhderlNATHCQYN 216
Cdd:cd15154  112 RPKVARLLCLAVWALILGGSVPAAI---VH-----SSSDCLLH 146