8JGD

GDP-bound KRAS G12C in complex with YK-8S

Summary for 8JGD

• Entry DOI: 10.2210/pdb8jgd/pdb
• Descriptor: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: hydrolase/inhibitor, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 20566.22

Authors

Zhang, Z.M.,Wang, R.L. (deposition date: 2023-05-20, release date: 2024-01-31)

Primary citation

Yu, Z.,He, X.,Wang, R.,Xu, X.,Zhang, Z.,Ding, K.,Zhang, Z.M.,Tan, Y.,Li, Z.
Simultaneous Covalent Modification of K-Ras(G12D) and K-Ras(G12C) with Tunable Oxirane Electrophiles.
J.Am.Chem.Soc., 145:20403-20411, 2023

PubMed Abstract: Owing to their remarkable pharmaceutical properties compared to those of noncovalent inhibitors, the development of targeted covalent inhibitors (TCIs) has emerged as a powerful method for cancer treatment. The K-Ras mutant, which is prevalent in multiple cancers, has been confirmed to be a crucial drug target in the treatment of various malignancies. However, although the K-Ras(G12D) mutation is present in up to 33% of K-Ras mutations, no covalent inhibitors targeting K-Ras(G12D) have been developed to date. The relatively weak nucleophilicity of the acquired aspartic acid (12D) residue in K-Ras may be the reason for this. Herein, we present the first compound capable of covalently engaging both K-Ras(G12D) and K-Ras(G12C) mutants. Proteome profiling revealed that this compound effectively conjugates with G12C and G12D residues, modulating the protein functions . These findings offer a unique pathway for the development of novel dual covalent inhibitors.

PubMed: 37534597
DOI: 10.1021/jacs.3c05899

Experimental method

X-RAY DIFFRACTION (1.60037058083 Å)