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CO-CRYSTAL STRUCTURE OF RAT PROTEIN FARNESYLTRANSFERASE COMPLEXED WITH A-176120
Structural highlights
FunctionFNTA_RAT 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). Publication Abstract from PubMedProtein prenylation is a post-translational modification promoting membrane association where isoprenoid lipids attach to C-terminal cysteines of eukaryotic proteins such as Ras and Rho GTPases, nucleus lamins, and G-protein subunits. Three enzymes catalyze this process: farnesyltransferase (FTase) and geranylgeranyltransferase type I and II (GGTase I and RabGGTase). FTase and GGTase-I recognize C-terminal CaaX motifs, of which the terminal amino acid confers specificity. Due to its involvement in oncogenic Ras activation, FTase has become a major anticancer target for drug development. Although first-generation FTase inhibitors failed in clinical trials in many cancers due to compensatory geranylgeranylation of KRAS and NRAS, they remain effective against HRAS-driven tumors and other pathologies, such as Hutchinson-Gilford progeria syndrome. The FTase inhibitor A-176120 was reported to compete with farnesyl and not KRAS. However, our crystallographic and biochemical analyses reveal that A-176120 sterically interferes with the engagement of the KRAS CAAX motif, reducing, but not abolishing, its binding to FTase. KRAS Can Bind to FTase Despite Disruption of the CAAX Binding Site.,Carion M, Cuesta R, Kowalczyk D, Smets W, Soons E, Klaassen H, Vanderhoydonck B, Marchand A, Versele M, Chaltin P, Dedecker P, Park H, Ismail S Biochemistry. 2026 Mar 3;65(5):521-526. doi: 10.1021/acs.biochem.5c00732. Epub , 2026 Feb 12. PMID:41680083[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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