7EWB

GDP-bound KRAS G12D in complex with TH-Z835

7EWB の概要

• エントリーDOI: 10.2210/pdb7ewb/pdb
• 分子名称: Isoform 2B of GTPase KRas, MAGNESIUM ION, GUANOSINE-5'-DIPHOSPHATE, ... (6 entities in total)
• 機能のキーワード: kras, g12d, salt-bridge, inhibitor, complex, th-z835, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 61217.04

構造登録者

Shen, P.,Yang, Y.,Yang, Y.,Zhang, L.,Chen, C.-C.,Guo, R.-T. (登録日: 2021-05-25, 公開日: 2021-12-29, 最終更新日: 2023-11-29)

主引用文献

Mao, Z.,Xiao, H.,Shen, P.,Yang, Y.,Xue, J.,Yang, Y.,Shang, Y.,Zhang, L.,Li, X.,Zhang, Y.,Du, Y.,Chen, C.C.,Guo, R.T.,Zhang, Y.
KRAS(G12D) can be targeted by potent inhibitors via formation of salt bridge.
Cell Discov, 8:5-5, 2022

PubMed Abstract: KRAS mutation occurs in nearly 30% of human cancers, yet the most prevalent and oncogenic KRAS(G12D) variant still lacks inhibitors. Herein, we designed a series of potent inhibitors that can form a salt bridge with KRAS's Asp12 residue. Our ITC results show that these inhibitors have similar binding affinity with both GDP-bound and GTP-bound KRAS(G12D), and our crystallographic studies reveal the structural basis of inhibitor binding-induced switch-II pocket in KRAS(G12D), experimentally confirming the formation of a salt bridge between the piperazine moiety of the inhibitors and the Asp12 residue of the mutant protein. Among KRAS family proteins and mutants, both ITC and enzymatic assays demonstrate the selectivity of the inhibitors for KRAS(G12D); and the inhibitors disrupt the KRAS-CRAF interaction. We also observed the inhibition of cancer cell proliferation as well as MAPK signaling by a representative inhibitor (TH-Z835). However, since the inhibition was not fully dependent on KRAS mutation status, it is possible that our inhibitors may have off-target effects via targeting non-KRAS small GTPases. Experiments with mouse xenograft models of pancreatic cancer showed that TH-Z835 significantly reduced tumor volume and synergized with an anti-PD-1 antibody. Collectively, our study demonstrates proof-of-concept for a strategy based on salt-bridge and induced-fit pocket formation for KRAS(G12D) targeting, which warrants future medicinal chemistry efforts for optimal efficacy and minimized off-target effects.

PubMed: 35075146
DOI: 10.1038/s41421-021-00368-w

実験手法

X-RAY DIFFRACTION (1.99 Å)