9O0N

Crystal structure of GDP-bound wild type KRAS in complex with MRTX1133

9O0N の概要

• エントリーDOI: 10.2210/pdb9o0n/pdb
• 分子名称: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (7 entities in total)
• 機能のキーワード: kras, ras, kras4b, oncoprotein
• 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: 20586.03

構造登録者

Bonsor, D.A.,Simanshu, D.K. (登録日: 2025-04-03, 公開日: 2026-01-21, 最終更新日: 2026-02-25)

主引用文献

Bonsor, D.A.,Finci, L.I.,Potter, J.R.,Young, L.C.,Wall, V.E.,Goldstein de Salazar, R.,Geis, K.R.,Stephens, T.,Finney, J.,Nissley, D.V.,McCormick, F.,Simanshu, D.K.
Structure of SHOC2-KRAS-PP1C complex reveals RAS isoform-specific determinants and insights into targeting complex assembly by RAS inhibitors.
Nat Commun, 17:1614-1614, 2026

PubMed Abstract: RAF activation is essential for MAPK signaling and is mediated by RAS binding and the dephosphorylation of a conserved phosphoserine by the SHOC2-RAS-PP1C complex. MRAS forms a high-affinity SHOC2-MRAS-PP1C (SMP) complex, while canonical RAS isoforms (KRAS, HRAS, NRAS) form analogous but lower-affinity assemblies. Yet, cancers driven by oncogenic KRAS, HRAS, or NRAS remain strongly SHOC2-dependent, suggesting that these weaker complexes contribute to tumorigenesis. To elucidate how canonical RAS proteins form lower-affinity ternary complexes, the cryo-EM structure of the SHOC2-KRAS-PP1C (SKP) complex stabilized by Noonan syndrome mutations is described. The SKP architecture is similar to the SMP complex but forms fewer contacts and buries less surface area due to the absence of MRAS-specific structural features in KRAS that enhance complex stability. RAS inhibitors MRTX1133 and RMC-6236 alter Switch-I/II conformations, thereby blocking SKP assembly more effectively than they disrupt preformed complexes. These RAS inhibitors do not affect SMP formation because they do not bind MRAS. Since MRAS is upregulated in resistance to KRAS inhibition, we characterize a MRAS mutant capable of binding MRTX1133. This MRAS mutant can form an SMP complex, but MRTX1133 blocks its assembly, demonstrating the feasibility of dual SKP and SMP targeting. Overall, our findings define isoform-specific differences in SHOC2-RAS-PP1C complex formation and support a strategy to prevent both SKP and SMP assemblies to overcome resistance in RAS-driven cancers.

PubMed: 41519889
DOI: 10.1038/s41467-026-68319-1

実験手法

X-RAY DIFFRACTION (1.4 Å)