8CX5

Crystal Structure of small molecule alpha,beta-ketoamide 4 covalently bound to K-Ras(G12R)

Summary for 8CX5

• Entry DOI: 10.2210/pdb8cx5/pdb
• Descriptor: Isoform 2B of GTPase KRas, MAGNESIUM ION, {(2S)-4-[(7P)-7-(8-chloronaphthalen-1-yl)-8-fluoro-2-{[(4R,7as)-tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-4-yl]-1-[(3S)-2,2,3-trihydroxybutanoyl]piperazin-2-yl}acetonitrile, ... (7 entities in total)
• Functional Keywords: inhibitor, signaling protein, signaling protein-inhibitor complex, signaling protein/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 41341.95

Authors

Zhang, Z.,Morstein, J.,Ecker, A.,Guiley, K.Z.,Shokat, K.M. (deposition date: 2022-05-19, release date: 2022-08-31, Last modification date: 2024-11-20)

Primary citation

Zhang, Z.,Morstein, J.,Ecker, A.K.,Guiley, K.Z.,Shokat, K.M.
Chemoselective Covalent Modification of K-Ras(G12R) with a Small Molecule Electrophile.
J.Am.Chem.Soc., 144:15916-15921, 2022

PubMed Abstract: mutations are one of the most common oncogenic drivers in human cancer. While small molecule inhibitors for the G12C mutant have been successfully developed, allele-specific inhibition for other hotspot mutants remains challenging. Here we report the discovery of covalent chemical ligands for the common oncogenic mutant K-Ras(G12R). These ligands bind in the Switch II pocket and irreversibly react with the mutant arginine residue. An X-ray crystal structure reveals an imidazolium condensation product formed between the α,β-diketoamide ligand and the ε- and η-nitrogens of arginine 12. Our results show that arginine residues can be selectively targeted with small molecule electrophiles despite their weak nucleophilicity and provide the basis for the development of mutant-specific therapies for K-Ras(G12R)-driven cancer.

PubMed: 36001446
DOI: 10.1021/jacs.2c05377

Experimental method

X-RAY DIFFRACTION (1.72 Å)