Loading
PDBj
MenuPDBj@FacebookPDBj@X(formerly Twitter)PDBj@BlueSkyPDBj@YouTubewwPDB FoundationwwPDBDonate
RCSB PDBPDBeBMRBAdv. SearchSearch help

9CT8

Tricomplex of Compound 2, KRAS G12D, and CypA

This is a non-PDB format compatible entry.
Summary for 9CT8
Entry DOI10.2210/pdb9ct8/pdb
DescriptorIsoform 2B of GTPase KRas, Peptidyl-prolyl cis-trans isomerase A, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (7 entities in total)
Functional Keywordskras, cypa, g12d, gtpase, tri-complex, inhibitor-complex, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
Biological sourceHomo sapiens (human)
More
Total number of polymer chains4
Total formula weight78087.09
Authors
Zhang, D.,Bar Ziv, T.,Knox, J.E.,Yano, J.K. (deposition date: 2024-07-24, release date: 2025-07-23, Last modification date: 2025-08-06)
Primary citationWeller, C.,Burnett, G.L.,Jiang, L.,Chakraborty, S.,Zhang, D.,Vita, N.A.,Dilly, J.,Kim, E.,Maldonato, B.,Seamon, K.,Eilerts, D.F.,Milin, A.,Marquez, A.,Spradlin, J.,Helland, C.,Gould, A.,Ziv, T.B.,Dinh, P.,Steele, S.L.,Wang, Z.,Mu, Y.,Chugh, S.,Feng, H.,Hennessey, C.,Wang, J.,Roth, J.,Rees, M.,Ronan, M.,Wolpin, B.M.,Hahn, W.C.,Holderfield, M.,Wang, Z.,Koltun, E.S.,Singh, M.,Gill, A.L.,Smith, J.A.M.,Aguirre, A.J.,Jiang, J.,Knox, J.E.,Wildes, D.
A neomorphic protein interface catalyzes covalent inhibition of RAS G12D aspartic acid in tumors.
Science, 389:eads0239-eads0239, 2025
Cited by
PubMed Abstract: Mutant RAS proteins are among the most prevalent drivers of human cancer, and the glycine to aspartic acid mutation at codon 12 (G12D) is the most common variant. Mutation-selective covalent inhibitors spare RAS in healthy tissue and enable extended pharmacodynamic effect, but covalent targeting of RAS is hindered by low nucleophilicity and high proteomic abundance of carboxylic acids. We overcame these challenges with compounds that bind cyclophilin A (CYPA) to create a neomorphic protein-protein interface between CYPA and active RAS that enables selective, enzyme-like rate enhancement of the covalent reaction between D12 and electrophilic warheads with exceptionally low intrinsic reactivity. This approach yielded orally bioavailable compounds with marked antitumor activity in multiple preclinical models of KRAS cancers, including the investigational agent zoldonrasib (RMC-9805) currently undergoing clinical evaluation (NCT06040541).
PubMed: 40705880
DOI: 10.1126/science.ads0239
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.28 Å)
Structure validation

239803

数据于2025-08-06公开中

PDB statisticsPDBj update infoContact PDBjnumon