1s63

Human protein farnesyltransferase complexed with L-778,123 and FPP

spinqualitylabelsall models 1s63, resolution 1.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 1s63 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.9Å Ligands: 778, FPP, FRU, GLC, PRD_900003, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function FNTA_HUMAN Catalyzes the transfer of a farnesyl or geranyl-geranyl moiety from farnesyl or geranyl-geranyl pyrophosphate to a cysteine at the fourth position from the C-terminus of several proteins having the C-terminal sequence Cys-aliphatic-aliphatic-X. The alpha subunit is thought to participate in a stable complex with the substrate. The beta subunit binds the peptide substrate. Through RAC1 prenylation and activation may positively regulate neuromuscular junction development downstream of MUSK (By similarity). Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Many signal transduction proteins that control growth, differentiation, and transformation, including Ras GTPase family members, require the covalent attachment of a lipid group by protein farnesyltransferase (FTase) or protein geranylgeranyltransferase type-I (GGTase-I) for proper function and for the transforming activity of oncogenic mutants. FTase inhibitors are a new class of potential cancer therapeutics under evaluation in human clinical trials. Here, we present crystal structures of the clinical candidate L-778,123 complexed with mammalian FTase and complexed with the related GGTase-I enzyme. Although FTase and GGTase-I have very similar active sites, L-778,123 adopts different binding modes in the two enzymes; in FTase, L-778,123 is competitive with the protein substrate, whereas in GGTase-I, L-778,123 is competitive with the lipid substrate and inhibitor binding is synergized by tetrahedral anions. A comparison of these complexes reveals that small differences in protein structure can dramatically affect inhibitor binding and selectivity. These structures should facilitate the design of more specific inhibitors toward FTase or GGTase-I. Finally, the binding of a drug and anion together could be applicable for developing new classes of inhibitors. Crystallographic analysis reveals that anticancer clinical candidate L-778,123 inhibits protein farnesyltransferase and geranylgeranyltransferase-I by different binding modes.,Reid TS, Long SB, Beese LS Biochemistry. 2004 Jul 20;43(28):9000-8. PMID:15248757 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Farnesyltransferase 3D structures

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