9HMR

KRAS-G12V-D92C covalently bound to BI-1830

This is a non-PDB format compatible entry.

Summary for 9HMR

• Entry DOI: 10.2210/pdb9hmr/pdb
• Descriptor: Isoform 2B of GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: kras covalent inhibitor, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 80841.47

Authors

van Tienen, L.M.,Zak, K.M.,Kessler, D.,Sellers, W.R. (deposition date: 2024-12-09, release date: 2025-12-24, Last modification date: 2026-03-04)

Primary citation

van Tienen, L.M.,Bayoumi, S.,Muneeruddin, K.,Leymarie, N.,Popa, A.,Shekhar, M.,Mueller, M.,Li, R.,Zak, K.M.,Chilukuri, H.,Kornfilt, D.J.P.,Atack, T.C.,Kesar, D.,Bian, Y.,Shaw, K.L.,Jandova, Z.,Trollmann, P.,Geist, L.,Stolt-Bergner, P.,Rumpel, K.,Kessler, D.,Sellers, W.R.
Systematic cysteine scanning identifies a druggable pocket in oncogenic KRAS.
Cell Chem Biol, 33:241-255.e8, 2026

PubMed Abstract: The discovery of druggable pockets within proteins that lack traditional active sites remains a significant challenge in the development of therapeutics. To address this, we developed Cysteine Mapping of Accessible Pockets (CysMAP), a method for identifying druggable pockets in proteins. CysMAP employs systematic pooled cysteine (Cys)-variant libraries screened against diverse covalent compound libraries by intact LC-MS. We applied CysMAP to 189 KRAS(G12D) variants, purifying KRAS Cys-variants and screening them against 47 covalent compounds, quantifying accessibility, and reactivity across KRAS(G12D). We discovered previously unidentified ligand-bound states of Cys-variants surrounding the KRAS switch-II pocket. Structural studies of the D92C variant in complex with the compound BI-1830 uncovered a distinct novel binding pocket, highlighting the inherent plasticity of the region between switch-II and α3, that can accommodate diverse chemical entities in various conformations. This method holds significant potential for advancing drug discovery efforts against elusive targets such as oncogenic RAS mutants.

PubMed: 41679298
DOI: 10.1016/j.chembiol.2026.01.007

Experimental method

X-RAY DIFFRACTION (1.5 Å)