EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	Structure of SHOC2-KRAS-PP1C complex reveals RAS isoform-specific determinants and insights into targeting complex assembly by RAS inhibitors.
ジャーナル・号・ページ	Nat Commun, Year 2026
掲載日	2026年1月10日
著者	Daniel A Bonsor / Lorenzo I Finci / Jacob R Potter / Lucy C Young / Vanessa E Wall / Ruby Goldstein de Salazar / Katie R Geis / Tyler Stephens / Joseph Finney / Dwight V Nissley / Frank McCormick / Dhirendra K Simanshu /
PubMed 要旨	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- ...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.
リンク	Nat Commun / PubMed:41519889
手法	EM (単粒子) / X線回折
解像度	1.4 - 3.0 Å
構造データ	70159 9o65 EMDB-70159, PDB-9o65: Cryo-EM structure of SHOC2-KRAS-PP1CA (SKP) complex 手法: EM (単粒子) / 解像度: 3.0 Å PDB-9o0n: Crystal structure of GDP-bound wild type KRAS in complex with MRTX1133 手法: X-RAY DIFFRACTION / 解像度: 1.4 Å PDB-9o0o: Crystal structure of GMPPNP-bound wild type KRAS in complex with MRTX1133 手法: X-RAY DIFFRACTION / 解像度: 1.9 Å PDB-9o0p: Crystal structure of GDP-bound mutant MRAS in complex with MRTX1133 手法: X-RAY DIFFRACTION / 解像度: 1.5 Å PDB-9o0q: Crystal structure of GMPPNP-bound mutant MRAS in complex with MRTX1133 手法: X-RAY DIFFRACTION / 解像度: 1.9 Å
化合物	ChemComp-GDP: GUANOSINE-5'-DIPHOSPHATE / GDP / GDP, エネルギー貯蔵分子YM ChemComp-MG: Unknown entry / マグネシウムジカチオン ChemComp-6IC: 4-(4-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-{[(2R,4R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol ChemComp-MPD: (4S)-2-METHYL-2,4-PENTANEDIOL / (S)-2-メチル-2,4-ペンタンジオ-ル / 沈殿剤YM ChemComp-CL: Unknown entry / クロリド ChemComp-HOH: WATER ChemComp-GNP: PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / Gpp(NH)p / GppNHp, GMPPNP, エネルギー貯蔵分子類似体YM ChemComp-GOL: GLYCEROL / グリセロ-ル ChemComp-SO4: SULFATE ION / 硫酸ジアニオン ChemComp-NA: Unknown entry / ナトリウムカチオン ChemComp-MN*: Unknown entry
由来	homo sapiens (ヒト)
キーワード	ONCOPROTEIN / KRAS / RAS / KRAS4B / MRAS / SIGNALING PROTEIN / SHOC2 / PP1CA