Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Structure of SHOC2-KRAS-PP1C complex reveals RAS isoform-specific determinants and insights into targeting complex assembly by RAS inhibitors.
Journal, issue, pages	Nat Commun, Year 2026
Publish date	Jan 10, 2026
Authors	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 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- ...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.
External links	Nat Commun / PubMed:41519889
Methods	EM (single particle) / X-ray diffraction
Resolution	1.4 - 3.0 Å
Structure data	70159 9o65 EMDB-70159, PDB-9o65: Cryo-EM structure of SHOC2-KRAS-PP1CA (SKP) complex Method: EM (single particle) / Resolution: 3.0 Å PDB-9o0n: Crystal structure of GDP-bound wild type KRAS in complex with MRTX1133 Method: X-RAY DIFFRACTION / Resolution: 1.4 Å PDB-9o0o: Crystal structure of GMPPNP-bound wild type KRAS in complex with MRTX1133 Method: X-RAY DIFFRACTION / Resolution: 1.9 Å PDB-9o0p: Crystal structure of GDP-bound mutant MRAS in complex with MRTX1133 Method: X-RAY DIFFRACTION / Resolution: 1.5 Å PDB-9o0q: Crystal structure of GMPPNP-bound mutant MRAS in complex with MRTX1133 Method: X-RAY DIFFRACTION / Resolution: 1.9 Å
Chemicals	ChemComp-GDP: GUANOSINE-5'-DIPHOSPHATE / GDP, energy-carrying moleculeYM ChemComp-MG: Unknown entry 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 / precipitantYM ChemComp-CL: Unknown entry ChemComp-HOH: WATER ChemComp-GNP: PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / GppNHp, GMPPNP, energy-carrying molecule analogueYM ChemComp-GOL: GLYCEROL ChemComp-SO4: SULFATE ION ChemComp-NA: Unknown entry ChemComp-MN*: Unknown entry
Source	homo sapiens (human)
Keywords	ONCOPROTEIN / KRAS / RAS / KRAS4B / MRAS / SIGNALING PROTEIN / SHOC2 / PP1CA