3DWB,3ZUK,1R1H,1DMT,4IUW


Conserved Protein Domain Family
M13

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cd08662: M13 
Click on image for an interactive view with Cn3D
Peptidase family M13 includes neprilysin and endothelin-converting enzyme I
The M13 family of metallopeptidases includes neprilysin (neutral endopeptidase, NEP, enkephalinase, CD10, CALLA, EC 3.4.24.11), endothelin-converting enzyme I (ECE-1, EC 3.4.24.71), erythrocyte surface antigen KELL (ECE-3), phosphate-regulating gene on the X chromosome (PHEX), soluble secreted endopeptidase (SEP), and damage-induced neuronal endopeptidase (DINE)/X-converting enzyme (XCE). Proteins in this family fulfill a broad range of physiological roles due to the greater variation in the active site's S2' subsite allowing substrate specificity. NEP is expressed in a variety of tissues including kidney and brain, and is involved in many physiological and pathological processes, including blood pressure and inflammatory response. It degrades a wide array of substrates such as substance P, enkephalins, cholecystokinin, neurotensin and somatostatin. It is an important enzyme in the regulation of amyloid-beta (Abeta) protein that forms amyloid plaques that are associated with Alzeimers disease (AD). ECE-1 catalyzes the final rate-limiting step in the biosynthesis of endothelins via post-translational conversion of the biologically inactive big endothelins. Like NEP, it also hydrolyzes bradykinin, substance P, neurotensin, and Abeta. Endothelin-1 overproduction has been implicated in various diseases including stroke, asthma, hypertension, and cardiac and renal failure. Kell is a homolog of NEP and constitutes a major antigen on human erythrocytes; it preferentially cleaves big endothelin-3 to produce bioactive endothelin-3, but is also known to cleave substance P and neurokinin A. PHEX forms a complex interaction with fibroblast growth factor 23 (FGF23) and matrix extracellular phosphoglycoprotein, causing bone mineralization. A loss-of-function mutation in PHEX disrupts this interaction leading to hypophosphatemic rickets; X-linked hypophosphatemic (XLH) rickets is the most common form of metabolic rickets. ECEL1 is a brain metalloprotease which plays a critical role in the nervous regulation of the respiratory system, while DINE is abundantly expressed in the hypothalamus and its expression responds to nerve injury. A majority of these M13 proteases are prime therapeutic targets for selective inhibition.
Statistics
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PSSM-Id: 341056
Aligned: 733 rows
Threshold Bit Score: 253.059
Created: 19-Nov-2009
Updated: 2-Oct-2020
Structure
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Program:
Drawing:
Aligned Rows:
 
Zn binding siteactive site
Conserved site includes 3 residues -Click on image for an interactive view with Cn3D
Feature 1: Zn binding site [ion binding site], 3 residue positions
Conserved feature residue pattern:H H EClick to see conserved feature residue pattern help
Evidence:
  • Structure:3DWB: human endothelin-converting enzyme I binds Zn2+
  • Structure:3ZUK: Mycobacterium tuberculosis Zinc Metalloprotease Zmp1 binds Zn
  • Comment:generally in GluZincins, the zinc ion is tetrahedrally co-ordinated by three amino acid ligands and a water molecule, however in this structure-inhibitor complex the water molecule is replaced by the His side chain

Sequence Alignment
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Format: Row Display: Color Bits: Type Selection:
Feature 1                                                                                        
3DWB_A        19 VDPCHDFFSYACGGWIKANpvpdghsrwGTFSNLWEHNQAIIKHllensta--svseaerKAQVYYRACMNetrie---- 92   human
CAG05447      25 VNPCDDFYTFACGGWIKENpipedsssyGIYPWLRQEVDIRLKElleapada-aeleavgKAKVLYRSCMNetvle---- 99   spotted green ...
AOT86841       8 TDPCDNFFRFSCAGWVRANpipedastyGTYSHVRKQVDLKLKEllerdsdehteleairRAKVMYRSCMNeslie---- 83   sea lamprey
KFP13332      72 VDPCENFYRFACDGWIYNHpipedmsnyGVYPWLRHNVDLKLKAllekpiskrrdseavqKAKTLYASCMNenkie---- 147  little egret
P78562        74 VDPCDNFFRFACDGWISNNpipedmpsyGVYPWLRHNVDLKLKElleksisrrrdteaiqKAKILYSSCMNekaie---- 149  human
OCT94190      75 IDPCEDFFEYACGGWIEENpipddmsnyGIYPWLRANVDLKLKAllekpiskrrdseaiqKVKTFYISCMNetqve---- 150  African clawed...
ESN97650      11 VDPCQDFYAYACGSWIKNAtipedsykvDRFNEMNDLTENRLKAllsttnp--sditsvlNAKKFYKSCLNqnqia---- 84   Helobdella rob...
XP_002128536 270 VDPCDDFYDYSCGRWFKETkipeskghyLTYTVLRDRVNKDVAGelakpika-segtavaKVKTAYKACMDtatin---- 344  Ciona intestin...
KJH48374      48 IDPCENFYQFACAKWLLRHpvsidqkaySNFNTIEDKVSKQIRGilgsqei--pksksirAFKTIYHKCMDesein---- 121  bovine lungworm
KOF96659      95 VDPCHDFYQYTCGNWVRDNpipenyaswDRFQELSEKNLYRLKGllenlql---igpleqKVKNFYNSCLLesdgfkqdi 171  Octopus bimacu...
Feature 1                                                                                        
3DWB_A        93 -elraKPLMELIerlggwnitgpwakdnf----------------------------qdtlqvvtahyrtspfFSVYVSA 143  human
CAG05447     100 -kldsKPMLKTLkqpefrwpvvgdglkgeyqwsa------------------gqwsllktladmrnlhsksvlVRLYVSP 160  spotted green ...
AOT86841      84 -dldtAPLLQLLshpmlrwpvlsstvgcrdsseglaacphrepsseaepwdagafdlretlavlsrnfshsilMSLHLGT 162  sea lamprey
KFP13332     148 -kadvKPLLSILrhspfrwpvlesnigpegvwse------------------rrfslvqalatlrgqysnsvfIRLYVAA 208  little egret
P78562       150 -kadaKPLLHILrhspfrwpvlesnigpegvwse------------------rkfsllqtlatfrgqysnsvfIRLYVSP 210  human
OCT94190     151 -vddiKPIVKILkqpslrwpvlesnigsdgkwse------------------rkfnflqtladlrrlystsvfLRVYVAI 211  African clawed...
ESN97650      85 -segiKPFKDIIdsfggcpalnaekfdesrw------------------------mledvvsriqktliydtiLKGILVP 139  Helobdella rob...
XP_002128536 345 -rkggKPLLDFLkgdlawpii--------------------------------------------detwspssFDLESTL 379  Ciona intestin...
KJH48374     122 -lngaRRFLDTVrf---------------------------------------------------------ipHTLGLVS 143  bovine lungworm
KOF96659     172 rkktlDSLRKLIhkvggwslknatnntilyp-----------------------ewtfesvlleihlldiwplFRITVDV 228  Octopus bimacu...
Feature 1                                                                                        
3DWB_A       144 DSKnsn----------------snVIQVDQSglglpsrdyyl-nktenekvltgYLNYMVQLGkllgggde--------- 197  human
CAG05447     161 DDKnss----------------hyVIKLDQAslslpsredy----ttnsssaqaYRAALLSLMvdvavmlga-------p 213  spotted green ...
AOT86841     163 DDKssa----------------hyILKFDQAslilparedy----ttnstqavtHRQALLRLLvdialmlga-------e 215  sea lamprey
KFP13332     209 DDKisn----------------ryILKLDQAslslasredy----lentteaksYRDAFLQFMvdtavllga-------n 261  little egret
P78562       211 DDKasn----------------ehILKLDQAtlslavredy----ldnsteaksYRDALYKFMvdtavllga-------n 263  human
OCT94190     212 DDKvsn----------------nfILKLDQAslsllshedy----ldnstiakkYKDALLEFMvdvavllga-------n 264  African clawed...
ESN97650     140 DREnsd----------------iiLFSLGQVnflltkaqys----dsntkyidaYFNYMVGVMqaisdnp---------- 189  Helobdella rob...
XP_002128536 380 ATLrgrynnqiltkivarrtsgnhILELWKGkmalpfsyye---meekkpkldaYYALMRDTAvmlgadr---------- 446  Ciona intestin...
KJH48374     144 HEP---------------------YLNKDKPnrl-----------------ldgYRQLIINKIklfyndanip-----id 180  bovine lungworm
KOF96659     229 DEMdlsr--------------nifKIGIGSNfldshrhplssnqgnetslhgqlYSQYLKESFdrylketirimelfigk 294  Octopus bimacu...
Feature 1                                                                                        
3DWB_A       198 -eairpqmQQILDFETALANItipqekrrdeelIYHKVtaaelqtlapaINWLPFLNtifypve-------inesepIVV 269  human
CAG05447     214 ekaaqaqmEQALAFETKIAHIlvpyen-rtsenMYNRYsisrlhrhipeFDWLGFIKrvvetkedk--srsisssehVIV 290  spotted green ...
AOT86841     216 srtahedmGAILNFEVQLANIlvpren-rtseaLYNRYtvaelqdlipqFDWLRFMKaaidtqerypelnalnssepVIV 294  sea lamprey
KFP13332     262 asraesdmKSVLRLEVKIAEImipyen-rtsevMYNKMsiselsamipqFDWLGYITkvidtrlype-lkdigpsenVIV 339  little egret
P78562       264 ssraehdmKSVLRLEIKIAEImiphen-rtseaMYNKMniselsamipqFDWLGYIKkvidtrlyph-lkdispsenVVV 341  human
OCT94190     265 ktraetdmKALIELETKLAQItvpqen-rtsemMYNKMniselsamipqFDWLSYLKnvidfkihpe-lknidssenVII 342  African clawed...
ESN97650     190 -qtvqqdmSAVLNLEKKLVQFfkntde-tskkeAYNKIlyknl--dstkFNWKLYLNniipny--------fvddtpIVT 257  Helobdella rob...
XP_002128536 447 -atanrdvADVKRFEKELAFHkihdld-yfsikTIDQMmee-----ipgIDWLRLFSlmiishp-------ingntqIEV 512  Ciona intestin...
KJH48374     181 etkvakdvDDIIALETKLAEIqaatvnadftreRLSKLqkl-----vplVKWSEYFHsitpfath----hyingdpiVMI 251  bovine lungworm
KOF96659     295 svnvskmaYEVSLMEKTLVQMkslt-----ateSYNVStihdllirypaINWIKYFQslatirni-----kiqnsdrVAI 364  Octopus bimacu...
Feature 1                                                                                        
3DWB_A       270 YdKEYLEqist-----lintTDRCLLNNYMIWNLVRKtssfldqrfqdade-kfmevmygtkktslPRWKFCVSDTENnL 343  human
CAG05447     291 RvPQYFKdlfk-----linsTDPRIVANYVQWRTVFSritslsrrflyryl--dfarvttgttsltPRWDKCVNFVEGsL 363  spotted green ...
AOT86841     295 CvPTYFQslfe-----llghTDKRVVANYVVGRLVMNrvrslsqrflqrhl--qfhqvvmgtrsvqARWDLCVNLVEAmM 367  sea lamprey
KFP13332     340 RvPQYFKdlfr-----ilenERKKTLANYLVWRMVYSrlfnlsrrfqyrwl--efsrvihgtttllPQWEKCVDLVENaL 412  little egret
P78562       342 RvPQYFKdlfr-----ilgsERKKTIANYLVWRMVYSripnlsrrfqyrwl--efsrviqgtttllPQWDKCVNFIESaL 414  human
OCT94190     343 RvPQHFKdlfn-----iiesEEKRTLANYLIWRFVYSripnlsrrfqyrql--eyarillgtnslaGRWDRCVNYVENsI 415  African clawed...
ESN97650     258 TeKEYLIeman-----ivqtTPKRTLANFVIWSVVRRmfnnfflpaqlkahyntfitvmtgaikevPIDTQCEQMTAKyF 332  Helobdella rob...
XP_002128536 513 WnQQFLNniia-----lidrTDKRVVQNYLIWRIVKHrilnlshkflvrys--qykkilygtkvlpTREHKCAQQLMFtM 585  Ciona intestin...
KJH48374     252 N-SDFITrvnd-----llqsVDSKIITNYVYMYFSKSwrgelgqryediqq--efekyvfrsstkePRWKYCLRTVQEeM 323  bovine lungworm
KOF96659     365 LyPDYLShlsvflndvksniTKAETLQNYLIVTLMRSmlpffqesnle--------edekdsrkplDNWKRCIFYTNKaL 436  Octopus bimacu...
Feature 1                                                                                        
3DWB_A       344 GFALGPMFvk--------atFAEDSKSIATEIILEIKKAFEesls-tlkwMDEETRKSAKEKadaIYNMIGYPNFi-mDP 413  human
CAG05447     364 SYATGRIFvdkhfqedkklvSALLRMAQMEELIEGIRWAFIdilekendwMDPPTKKKAIEKahaVLPKVGYPEFi-lNN 442  spotted green ...
AOT86841     368 PSVMGRLFvd--------ahFQEEKKELMEKLVDGIRWAFVdmletentwMDVPTKQKATEKadaVLARMGYPDYi-kNN 438  sea lamprey
KFP13332     413 PYVVGKMFvn--------ahFQEDKKEMMEELTEGIRWAFIdmlekendwMDSETKRKAYEKakaVMAKVGYPQFi-mND 483  little egret
P78562       415 PYVVGKMFvd--------vyFQEDKKEMMEELVEGVRWAFIdmlekenewMDAGTKRKAKEKaraVLAKVGYPEFi-mND 485  human
OCT94190     416 PYPVGKLFvd--------ahFQEDKKDMMEELIDGIRWAFIdmlekendwMDEVTKTKAKEKaatVMAKVGYPEFl-fNE 486  African clawed...
ESN97650     333 GEPLSRIYve--------kyIQQDIMDLVIDMVDRMVYEFKnlir-snkwMDDSTKEEALVKlnlMSRKVGYPDYl-fNN 402  Helobdella rob...
XP_002128536 586 KGATGNLFin--------kyFSPAKKRAAHLMFENIRKGFLqllgtevdwMDDKTKNYAKRKaeaIKAVFGYNAHiyrNI 657  Ciona intestin...
KJH48374     324 KLVSGALYe-----------TINATMEIVEDIMSSFREILHen-----ewINEAMKTKVLNKlklMRRQIGYPEFi-lDD 386  bovine lungworm
KOF96659     437 GFATGAIYvka-------atKGREIHDKIENLIKYIKEAFKayil-rkfwMDKYTKAAAAAKldsMIEKVSYPSFm-lNT 507  Octopus bimacu...
Feature 1                                                                                        
3DWB_A       414 KELDKVFndyta-vpdlyFENAMRFFNFSWRVTADqlrkaPNRDQWSMTPp--mVNAYYSptkNEIVFPAg-ILQAP-FY 488  human
CAG05447     443 TYLNEDLkklqf-sekdyYGNVMQTLKFIGQSDLAwlrktVPRTEWFTNPt--tVNAFYSsstNQIRFPAg-ELQKPfFW 518  spotted green ...
AOT86841     439 TYINEEVkmlrl-reddyFGNVLQLLQNMAQHDFHwlrrrVSKTEWYTNPt--tVNAFYSattNQILFPAg-ELQKPfFW 514  sea lamprey
KFP13332     484 TYINEDIktlkf-tesdyFGNVLQTRKHTAQSDFYwlrkeVPKTEWFTSPt--tVNAFYSastNQIRFPAg-ELQKPfFW 559  little egret
P78562       486 THVNEDLkaikf-seadyFGNVLQTRKYLAQSDFFwlrkaVPKTEWFTNPt--tVNAFYSastNQIRFPAg-ELQKPfFW 561  human
OCT94190     487 TYLNEDIkmlkf-sesdyFGNVLQTLYFISQSDFHwlrkeVPKKEWFTNPt--tVNAFYSastNQIRFPAg-ELQKPfFW 562  African clawed...
ESN97650     403 TFLDSTYgkmqi-denqhTKNMLNVLKYSFEHVKNmifkpYDKSLWSLDPi--kVAAQYSsqtNDIGAQLgnNIQHD-FV 478  Helobdella rob...
XP_002128536 658 TYIDEHMkhlvv-yendyFGNTVRILTQISQNSFHllgkeYQRGTYYFHTrpteVNAFYNpsyNEVVMPAg-ELQYP-FY 734  Ciona intestin...
KJH48374     387 RMLDDYYsglnvyesesyTQGKENLLAWSIRKSFLelinpHDKSDFTVDPa--lVNAFYSpqsNSIVFPAa-ILQEP-YF 462  bovine lungworm
KOF96659     508 TFLNNYYkqfdv-lesswFTNLINWKKFDLEKMIAqliekPDRRRWISPPv--tVSPFYSpirNELFFPMa-LFHLP-FF 582  Octopus bimacu...
Feature 1                            #   #                                                       
3DWB_A       489 TRssp--kaLNFGGIGVVVGHELTHAFDDQGReydkdgnlrpwWKNSSVEAFKRQTECMVeqysnysvn-----gepvng 561  human
CAG05447     519 GKeyp--rsLSYGAIGVIVGHELTHGFDSNGRkydsngnldqwWSNSSITAFSEKTQCMIdqynsyywekaglnvrgvrg 596  spotted green ...
AOT86841     515 GDkyp--msLNYGAIGVIVGHEFTHGFDNNGRkydkhgnlhqwWSNTSIARFSEKAQCMIeqynnyywke---aqlplkg 589  sea lamprey
KFP13332     560 GTeyp--rsLSYGAIGVIVGHEFTHGFDSNGRkydkngnldpwWTTDSEEKFKEKTKCMInqysnyywkr---aglhvkg 634  little egret
P78562       562 GTeyp--rsLSYGAIGVIVGHEFTHGFDNNGRkydkngnldpwWSTESEEKFKEKTKCMInqysnyywkk---aglnvkg 636  human
OCT94190     563 GVqyp--rsLSYGAIGVIVGHEFTHGFDNNGRkydkegnllswWTSESEERFKNKTQCVVdqynnyywkq---aglhvkg 637  African clawed...
ESN97650     479 VMiykgsapMNYGAFGMFIGHEISHGFDISGKlydgygnmrnwWSNSSDVLYKEKTDCLVrkynnfwikq---igeylng 555  Helobdella rob...
XP_002128536 735 WGdqf-pqmFQYGGVGTILGHELTHGFDNNGRkhgihghmynwWTQKSLEEFNKRTKCMEnqynkfywrt---agsylng 810  Ciona intestin...
KJH48374     463 HQsfp--kaLNYGALGSVIGHEITHAFDNKGRlydaegnlrdwWDGDVEKKFVERSKCFIeqyskievv----qgvning 536  bovine lungworm
KOF96659     583 SEegp--qsLNFGAIGSVIGHEITHAFGIRGMhydgngqlrnwWNPDTAKKFNITTQCVRktyssyqve-----hlyvdg 655  Octopus bimacu...
Feature 1             #                                                                          
3DWB_A       562 rhTLGENIADNGGLKAAyRAYQNWvkkngae---hslptlgLTNNQLFFLGFAQVWCsvrtpessheglitdPHSPSRFR 638  human
CAG05447     597 krTLAENIADNGGIREAfRAYRRWidtsrggaeelllpgvgLNNNQLFFLSYAHVRCnsyrpetareqiqsgAHSPPKFR 676  spotted green ...
AOT86841     590 krTLGENIADSGGVREAfRAYRKWikdsrggqeepllpglnLTHNQLFFISYAHVRCqahrpgearqmvlvgAHSPPEFR 669  sea lamprey
KFP13332     635 krTLAENIADNGGLREAfRAYRRWitekrggeeepllpgleFTHNQLFFLSYAHVRCnsfrpesareqiyigAHSPPQFR 714  little egret
P78562       637 krTLGENIADNGGLREAfRAYRKWindrrqgleepllpgitFTNNQLFFLSYAHVRCnsyrpeaareqvqigAHSPPQFR 716  human
OCT94190     638 tkTLSENIADNGGMRESfRAYRKWiedsrkgkeelllpgldLNNNQLFFISYAHVRCnsfriesardqvmngVHSPPQFR 717  African clawed...
ESN97650     556 esTLGENIADFVGLQIAyQTYRNSmkkgdsak--eklpglqFTSDQLFFISFAQFWCekmsneg-fqlmkrdDHSPNIAR 632  Helobdella rob...
XP_002128536 811 hkTLGENIADNGGIRESyTGYHIWlksqnltg-eslepstgLTNDQLFFIGFANVRCgkythagaaninavdVHSPGRFR 889  Ciona intestin...
KJH48374     537 trSLGENIADNGGVKQAfRAYAKYlkkfgnek--rlkgleeFSNEQMFFIAYAKAFCgnlhisalinrvyhdTHTPYEYR 614  bovine lungworm
KOF96659     656 evTLDENIADNGGLRAAyVAYLLWteengie---kplpgldLTPTQLFYVSFAQMYCsawtkeglkhhlltdHFAPGKAR 732  Octopus bimacu...
Feature 1                                       
3DWB_A       639 VIGSLSNsKEFSEHFRCppgsp-mnppHKCE 668  human
CAG05447     677 VIGAMSNyEEFWKAFGCpassvmnrgaQSCR 707  spotted green pufferfish
AOT86841     670 VLGSMSNfPEFARAFQCaegttmnrgkQACR 700  sea lamprey
KFP13332     715 VIGAMSNfEEFRKAFNCpsnttmnrgaESCR 745  little egret
P78562       717 VNGAISNfEEFQKAFNCppnstmnrgmDSCR 747  human
OCT94190     718 VIGAMSNfEEFHKVFNCpknskmnrgnKSCR 748  African clawed frog
ESN97650     633 VTVPLQNfEKFAFVFNCpktsp-mnspDKCK 662  Helobdella robusta
XP_002128536 890 VIGSLQNfDKFSKAFNCpvgsk-mnpkHKCI 919  Ciona intestinalis
KJH48374     615 VNQALANqPEFASAFRCsagtp-mnpaKRCV 644  bovine lungworm
KOF96659     733 VIGAISNsRAFSSVFDCpftsa-mnpsTKCE 762  Octopus bimaculoides

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