5V6V

Crystal structure of small molecule aziridine 3 covalently bound to K-Ras G12C

5V6V の概要

• エントリーDOI: 10.2210/pdb5v6v/pdb
• 関連するPDBエントリー: 5v6s
• 分子名称: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, CALCIUM ION, ... (6 entities in total)
• 機能のキーワード: k-ras g12c, covalent inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 40860.39

構造登録者

McGregor, L.M.,Jenkins, M.,Kerwin, C.,Burke, J.E.,Shokat, K.M. (登録日: 2017-03-17, 公開日: 2017-06-28, 最終更新日: 2024-10-23)

主引用文献

McGregor, L.M.,Jenkins, M.L.,Kerwin, C.,Burke, J.E.,Shokat, K.M.
Expanding the Scope of Electrophiles Capable of Targeting K-Ras Oncogenes.
Biochemistry, 56:3178-3183, 2017

PubMed Abstract: There is growing interest in reversible and irreversible covalent inhibitors that target noncatalytic amino acids in target proteins. With a goal of targeting oncogenic K-Ras variants (e.g., G12D) by expanding the types of amino acids that can be targeted by covalent inhibitors, we survey a set of electrophiles for their ability to label carboxylates. We functionalized an optimized ligand for the K-Ras switch II pocket with a set of electrophiles previously reported to react with carboxylates and characterized the ability of these compounds to react with model nucleophiles and oncogenic K-Ras proteins. Here, we report that aziridines and stabilized diazo groups preferentially react with free carboxylates over thiols. Although we did not identify a warhead that potently labels K-Ras G12D, we were able to study the interactions of many electrophiles with K-Ras, as most of the electrophiles rapidly label K-Ras G12C. We characterized the resulting complexes by crystallography, hydrogen/deuterium exchange, and differential scanning fluorimetry. Our results both demonstrate the ability of a noncatalytic cysteine to react with a diverse set of electrophiles and emphasize the importance of proper spatial arrangements between a covalent inhibitor and its intended nucleophile. We hope that these results can expand the range of electrophiles and nucleophiles of use in covalent protein modulation.

PubMed: 28621541
DOI: 10.1021/acs.biochem.7b00271

実験手法

X-RAY DIFFRACTION (1.72 Å)