9CTB
Tri-complex of zoldonrasib (RMC-9805), KRAS G12D, and CypA
This is a non-PDB format compatible entry.
Summary for 9CTB
| Entry DOI | 10.2210/pdb9ctb/pdb |
| Descriptor | Peptidyl-prolyl cis-trans isomerase A, Isoform 2B of GTPase KRas, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (7 entities in total) |
| Functional Keywords | kras, cypa, g12d, gtpase, tri-complex, inhibitor-complex, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 78585.72 |
| Authors | Zhang, D.,Bar Ziv, T.,Tomlinson, A.C.A.,Saldajeno-Concar, M.,Yano, J.K.,Knox, J.E. (deposition date: 2024-07-24, release date: 2025-07-23, Last modification date: 2025-08-06) |
| Primary citation | Weller, 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: 40705880DOI: 10.1126/science.ads0239 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.29 Å) |
Structure validation
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