9O0P
Crystal structure of GDP-bound mutant MRAS in complex with MRTX1133
Summary for 9O0P
| Entry DOI | 10.2210/pdb9o0p/pdb |
| Descriptor | Ras-related protein M-Ras, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (6 entities in total) |
| Functional Keywords | mras, ras, oncoprotein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 43085.88 |
| Authors | |
| Primary citation | 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, 2026 Cited by 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: 41519889DOI: 10.1038/s41467-026-68319-1 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.5 Å) |
Structure validation
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