7A1W

KRASG12C GDP form in complex with Cpd3

7A1W の概要

• エントリーDOI: 10.2210/pdb7a1w/pdb
• 分子名称: Isoform 2B of GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (6 entities in total)
• 機能のキーワード: inhibitor, mutant, oncoprotein
• 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: 20530.11

構造登録者

Mathieu, M.,Steier, V. (登録日: 2020-08-14, 公開日: 2021-10-13, 最終更新日: 2024-11-20)

主引用文献

Mathieu, M.,Steier, V.,Fassy, F.,Delorme, C.,Papin, D.,Genet, B.,Duffieux, F.,Bertrand, T.,Delarbre, L.,Le-Borgne, H.,Parent, A.,Didier, P.,Marquette, J.P.,Lowinski, M.,Houtmann, J.,Lamberton, A.,Debussche, L.,Alexey, R.
KRAS G12C fragment screening renders new binding pockets.
Small Gtpases, 13:225-238, 2022

PubMed Abstract: KRAS genes belong to the most frequently mutated family of oncogenes in cancer. The G12C mutation, found in a third of lung, half of colorectal and pancreatic cancer cases, is believed to be responsible for a substantial number of cancer deaths. For 30 years, KRAS has been the subject of extensive drug-targeting efforts aimed at targeting KRAS protein itself, but also its post-translational modifications, membrane localization, protein-protein interactions and downstream signalling pathways. So far, most KRAS targeting strategies have failed, and there are no KRAS-specific drugs available. However, clinical candidates targeting the KRAS G12C protein have recently been developed. MRTX849 and recently approved Sotorasib are covalent binders targeting the mutated cysteine 12, occupying Switch II pocket.Herein, we describe two fragment screening drug discovery campaigns that led to the identification of binding pockets on the KRAS G12C surface that have not previously been described. One screen focused on non-covalent binders to KRAS G12C, the other on covalent binders.

PubMed: 34558391
DOI: 10.1080/21541248.2021.1979360

実験手法

X-RAY DIFFRACTION (1.76 Å)