1sa4 | pdb_00001sa4

human protein farnesyltransferase complexed with FPP and R115777

spinqualitylabelsall models 1sa4, resolution 2.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 1sa4 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: FPP, GLC, JAN, ZN, FRU Related: 1d8d, 1ft1, 1jcq, 1jcr, 1o5m, 1ld8, 1sa5 Gene: FNTA (HUMAN), FNTB (HUMAN) Activity: Protein farnesyltransferase, with EC number 2.5.1.58 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). [FNTB_HUMAN] Catalyzes the transfer of a farnesyl moiety from farnesyl pyrophosphate to a cysteine at the fourth position from the C-terminus of several proteins. The beta subunit is responsible for peptide-binding. 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 The search for new cancer therapeutics has identified protein farnesyltransferase (FTase) as a promising drug target. This enzyme attaches isoprenoid lipids to signal transduction proteins involved in growth and differentiation. The two FTase inhibitors (FTIs), R115777 (tipifarnib/Zarnestra) and BMS-214662, have undergone evaluation as cancer therapeutics in phase I and II clinical trials. R115777 has been evaluated in phase III clinical trials and shows indications for the treatment of blood and breast malignancies. Here we present crystal structures of R115777 and BMS-214662 complexed with mammalian FTase. These structures illustrate the molecular mechanism of inhibition and selectivity toward FTase over the related enzyme, protein geranylgeranyltransferase type I (GGTase-I). These results, combined with previous biochemical and structural analyses, identify features of FTase that could be exploited to modulate inhibitor potency and specificity and should aid in the continued development of FTIs as therapeutics for the treatment of cancer and parasitic infections. Crystal structures of the anticancer clinical candidates R115777 (Tipifarnib) and BMS-214662 complexed with protein farnesyltransferase suggest a mechanism of FTI selectivity.,Reid TS, Beese LS Biochemistry. 2004 Jun 8;43(22):6877-84. PMID:15170324 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Farnesyltransferase 3D structures

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