8JGD

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

8JGD の概要

• エントリーDOI: 10.2210/pdb8jgd/pdb
• 分子名称: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: hydrolase/inhibitor, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 20566.22

構造登録者

Zhang, Z.M.,Wang, R.L. (登録日: 2023-05-20, 公開日: 2024-01-31, 最終更新日: 2024-11-13)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.60037058083 Å)