5VBZ

Crystal Structure of Small Molecule Disulfide 2C07 Bound to H-Ras M72C GppNHp

5VBZ の概要

• エントリーDOI: 10.2210/pdb5vbz/pdb
• 分子名称: GTPase HRas, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: gtpase, inhibitor, gdp, hydrolase
• 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: 3
• 化学式量合計: 59750.65

構造登録者

Gentile, D.R.,Jenkins, M.L.,Moss, S.M.,Burke, J.E.,Shokat, K.M. (登録日: 2017-03-30, 公開日: 2017-10-25, 最終更新日: 2024-11-20)

主引用文献

Gentile, D.R.,Rathinaswamy, M.K.,Jenkins, M.L.,Moss, S.M.,Siempelkamp, B.D.,Renslo, A.R.,Burke, J.E.,Shokat, K.M.
Ras Binder Induces a Modified Switch-II Pocket in GTP and GDP States.
Cell Chem Biol, 24:1455-1466.e14, 2017

PubMed Abstract: Covalent inhibitors of K-Ras(G12C) have been reported that exclusively recognize the GDP state. Here, we utilize disulfide tethering of a non-natural cysteine (K-Ras(M72C)) to identify a new switch-II pocket (S-IIP) binding ligand (2C07) that engages the active GTP state. Co-crystal structures of 2C07 bound to H-Ras(M72C) reveal binding in a cryptic groove we term S-IIG. In the GppNHp state, 2C07 binding to a modified S-IIP pushes switch I away from the nucleotide, breaking the network of polar contacts essential for adopting the canonical GTP state. Biochemical studies show that 2C07 alters nucleotide preference and inhibits SOS binding and catalyzed nucleotide exchange. 2C07 was converted to irreversible covalent analogs, which target both nucleotide states, inhibit PI3K activation in vitro, and function as occupancy probes to detect reversible engagement in competition assays. Targeting both nucleotide states opens the possibility of inhibiting oncogenic mutants of Ras, which exist predominantly in the GTP state in cells.

PubMed: 29033317
DOI: 10.1016/j.chembiol.2017.08.025

実験手法

X-RAY DIFFRACTION (2.2 Å)