7OK4

Crystal Structure of KRasG13C in Complex with Nucleotide-based covalent Inhibitor bdaGDP

7OK4 の概要

• エントリーDOI: 10.2210/pdb7ok4/pdb
• 分子名称: Isoform 2B of GTPase KRas, bdaGDP (3 entities in total)
• 機能のキーワード: gtpase, ras, kras, krasg13c, nucleotide analogues, bdagdp, 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: 20047.29

構造登録者

Goebel, L.,Mueller, M.P.,Rauh, D. (登録日: 2021-05-17, 公開日: 2022-08-03, 最終更新日: 2024-11-20)

主引用文献

Goebel, L.,Kirschner, T.,Koska, S.,Rai, A.,Janning, P.,Maffini, S.,Vatheuer, H.,Czodrowski, P.,Goody, R.S.,Muller, M.P.,Rauh, D.
Targeting oncogenic KRasG13C with nucleotide-based covalent inhibitors.
Elife, 12:-, 2023

PubMed Abstract: Mutations within Ras proteins represent major drivers in human cancer. In this study, we report the structure-based design, synthesis, as well as biochemical and cellular evaluation of nucleotide-based covalent inhibitors for KRasG13C, an important oncogenic mutant of Ras that has not been successfully addressed in the past. Mass spectrometry experiments and kinetic studies reveal promising molecular properties of these covalent inhibitors, and X-ray crystallographic analysis has yielded the first reported crystal structures of KRasG13C covalently locked with these GDP analogues. Importantly, KRasG13C covalently modified with these inhibitors can no longer undergo SOS-catalysed nucleotide exchange. As a final proof-of-concept, we show that in contrast to KRasG13C, the covalently locked protein is unable to induce oncogenic signalling in cells, further highlighting the possibility of using nucleotide-based inhibitors with covalent warheads in KRasG13C-driven cancer.

PubMed: 36972177
DOI: 10.7554/eLife.82184

実験手法

X-RAY DIFFRACTION (1.7 Å)