4L9S

Crystal Structure of H-Ras G12C, GDP-bound

4L9S の概要

• エントリーDOI: 10.2210/pdb4l9s/pdb
• 関連するPDBエントリー: 4L8G 4L9W 4LPK 4LRW 4LUC 4LV6 4LYF 4LYH 4LYJ 4M1O 4M1S 4M1T 4M1W 4M1Y 4M21 4M22
• 分子名称: GTPase HRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (6 entities in total)
• 機能のキーワード: gtpase, activating mutant, signaling protein
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cell membrane. Isoform 2: Nucleus: P01112
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 19918.38

構造登録者

Ostrem, J.M.,Peters, U.,Sos, M.L.,Wells, J.A.,Shokat, K.M. (登録日: 2013-06-18, 公開日: 2013-11-27, 最終更新日: 2023-09-20)

主引用文献

Ostrem, J.M.,Peters, U.,Sos, M.L.,Wells, J.A.,Shokat, K.M.
K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions.
Nature, 503:548-551, 2013

PubMed Abstract: Somatic mutations in the small GTPase K-Ras are the most common activating lesions found in human cancer, and are generally associated with poor response to standard therapies. Efforts to target this oncogene directly have faced difficulties owing to its picomolar affinity for GTP/GDP and the absence of known allosteric regulatory sites. Oncogenic mutations result in functional activation of Ras family proteins by impairing GTP hydrolysis. With diminished regulation by GTPase activity, the nucleotide state of Ras becomes more dependent on relative nucleotide affinity and concentration. This gives GTP an advantage over GDP and increases the proportion of active GTP-bound Ras. Here we report the development of small molecules that irreversibly bind to a common oncogenic mutant, K-Ras(G12C). These compounds rely on the mutant cysteine for binding and therefore do not affect the wild-type protein. Crystallographic studies reveal the formation of a new pocket that is not apparent in previous structures of Ras, beneath the effector binding switch-II region. Binding of these inhibitors to K-Ras(G12C) disrupts both switch-I and switch-II, subverting the native nucleotide preference to favour GDP over GTP and impairing binding to Raf. Our data provide structure-based validation of a new allosteric regulatory site on Ras that is targetable in a mutant-specific manner.

PubMed: 24256730
DOI: 10.1038/nature12796

実験手法

X-RAY DIFFRACTION (1.606 Å)