7L0F

Monobody 12VC3 Bound to HRAS(WT)

7L0F の概要

• エントリーDOI: 10.2210/pdb7l0f/pdb
• 分子名称: GTPase HRas, Monobody 12VC3, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: ras gtpase, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 119069.68

構造登録者

Teng, K.W.,Hattori, T.,Tsai, S.,Koide, S. (登録日: 2020-12-11, 公開日: 2021-03-24, 最終更新日: 2023-10-18)

主引用文献

Teng, K.W.,Tsai, S.T.,Hattori, T.,Fedele, C.,Koide, A.,Yang, C.,Hou, X.,Zhang, Y.,Neel, B.G.,O'Bryan, J.P.,Koide, S.
Selective and noncovalent targeting of RAS mutants for inhibition and degradation.
Nat Commun, 12:2656-2656, 2021

PubMed Abstract: Activating mutants of RAS are commonly found in human cancers, but to date selective targeting of RAS in the clinic has been limited to KRAS(G12C) through covalent inhibitors. Here, we report a monobody, termed 12VC1, that recognizes the active state of both KRAS(G12V) and KRAS(G12C) up to 400-times more tightly than wild-type KRAS. The crystal structures reveal that 12VC1 recognizes the mutations through a shallow pocket, and 12VC1 competes against RAS-effector interaction. When expressed intracellularly, 12VC1 potently inhibits ERK activation and the proliferation of RAS-driven cancer cell lines in vitro and in mouse xenograft models. 12VC1 fused to VHL selectively degrades the KRAS mutants and provides more extended suppression of mutant RAS activity than inhibition by 12VC1 alone. These results demonstrate the feasibility of selective targeting and degradation of KRAS mutants in the active state with noncovalent reagents and provide a starting point for designing noncovalent therapeutics against oncogenic RAS mutants.

PubMed: 33976200
DOI: 10.1038/s41467-021-22969-5

実験手法

X-RAY DIFFRACTION (1.98 Å)