28JN

CO-CRYSTAL STRUCTURE OF RAT PROTEIN FARNESYLTRANSFERASE COMPLEXED WITH A-176120

This is a non-PDB format compatible entry.

Summary for 28JN

• Entry DOI: 10.2210/pdb28jn/pdb
• Descriptor: Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha, Protein farnesyltransferase subunit beta, GLYCEROL, ... (6 entities in total)
• Functional Keywords: farnesyltransferase, protein prenylation, enzyme inhibitor complex, transferase
• Biological source: Rattus norvegicus (Norway rat); More
• Total number of polymer chains: 2
• Total formula weight: 93561.51

Authors

Cuesta, R.,Carion, M.,Park, H.W.,Ismail, S. (deposition date: 2026-02-03, release date: 2026-03-04)

Primary citation

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.
KRAS Can Bind to FTase Despite Disruption of the CAAX Binding Site.
Biochemistry, 2026

PubMed Abstract: Protein 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.

PubMed: 41680083
DOI: 10.1021/acs.biochem.5c00732

Experimental method

X-RAY DIFFRACTION (2.31 Å)