9DMM
Crystal structure of human KRAS G12C covalently bound to Divarasib (GDC6036)
This is a non-PDB format compatible entry.
Summary for 9DMM
| Entry DOI | 10.2210/pdb9dmm/pdb |
| Descriptor | Isoform 2B of GTPase KRas, 1-{(3S)-4-[(7M)-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-4-yl]-3-methylpiperazin-1-yl}propan-1-one, MAGNESIUM ION, ... (5 entities in total) |
| Functional Keywords | inhibitor, gtpase, complex, gdp, oncoprotein, hydrolase-inhibitor complex, hydrolase/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 20418.28 |
| Authors | Fernando, M.C. (deposition date: 2024-09-13, release date: 2025-05-21, Last modification date: 2025-05-28) |
| Primary citation | Fernando, M.C.,Craven, G.B.,Shokat, K.M. The structure of KRAS G12C bound to divarasib highlights features of potent switch-II pocket engagement. Small Gtpases, 15:1-7, 2024 Cited by PubMed Abstract: KRAS is the most frequently mutated oncogene in human cancer. In multiple types of cancer, a missense mutation at codon 12 substitutes a glycine for a cysteine, causing hyperactivation of the GTPase and enhanced MAPK signalling. Recent drug discovery efforts culminating from work during the past decade have resulted in two FDA-approved inhibitors, sotorasib and adagrasib, which target the KRAS mutant allele. Ongoing medicinal chemistry efforts across academia and industry have continued developing more potent and efficacious KRAS inhibitors. One agent in late-stage clinical trials, divarasib, has demonstrated robust overall response rates, in some cases greater than currently approved agents. Divarasib also exhibits enhanced covalent target engagement and significant specificity for KRAS, yet the structural details of its binding have not been published. Here we report a high-resolution crystal structure of cysteine-light KRAS-4B in complex with divarasib. Though it binds in the same allosteric pocket as sotorasib and adagrasib, the switch-II loop in each crystal structure takes on a distinct conformation differing as much as 5.6 Å between the Cα atom of residue 65 with sotorasib. Additionally, we highlight structural features of the drug complex that may guide future medicinal chemistry efforts targeting various alleles. PubMed: 40391409DOI: 10.1080/21541248.2025.2505441 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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