Abstract
Protein farnesyltransferase (FTase) catalyzes an essential posttranslational lipid modification of more than 60 proteins involved in intracellular signal transduction networks. FTase inhibitors have emerged as a significant target for development of anticancer therapeutics and, more recently, for the treatment of parasitic diseases caused by protozoan pathogens, including malaria (Plasmodium falciparum). We present the X-ray crystallographic structures of complexes of mammalian FTase with five inhibitors based on an ethylenediamine scaffold, two of which exhibit over 1000-fold selective inhibition of P. falciparum FTase. These structures reveal the dominant determinants in both the inhibitor and enzyme that control binding and selectivity. Comparison to a homology model constructed for the P. falciparum FTase suggests opportunities for further improving selectivity of a new generation of antimalarial inhibitors.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antimalarials / chemistry*
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Antimalarials / metabolism
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / metabolism
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Cell Line, Tumor
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Crystallography, X-Ray
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / metabolism
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Ethylenediamines / chemistry
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Farnesyltranstransferase / antagonists & inhibitors*
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Farnesyltranstransferase / chemistry*
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Farnesyltranstransferase / metabolism
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Humans
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Plasmodium falciparum / enzymology
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Protein Binding
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Protein Conformation
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Protozoan Proteins / antagonists & inhibitors
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Protozoan Proteins / chemistry
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Protozoan Proteins / metabolism
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Rats
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Structural Homology, Protein
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Structure-Activity Relationship
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Substrate Specificity
Substances
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Antimalarials
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Antineoplastic Agents
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Enzyme Inhibitors
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Ethylenediamines
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Protozoan Proteins
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ethylenediamine
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Farnesyltranstransferase