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'''Unreleased structure'''


The entry 9o65 is ON HOLD
==Cryo-EM structure of SHOC2-KRAS-PP1CA (SKP) complex==
<StructureSection load='9o65' size='340' side='right'caption='[[9o65]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9o65]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9O65 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9O65 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GNP:PHOSPHOAMINOPHOSPHONIC+ACID-GUANYLATE+ESTER'>GNP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9o65 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9o65 OCA], [https://pdbe.org/9o65 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9o65 RCSB], [https://www.ebi.ac.uk/pdbsum/9o65 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9o65 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/SHOC2_HUMAN SHOC2_HUMAN] Noonan syndrome-like disorder with loose anagen hair. The disease is caused by variants affecting the gene represented in this entry.
== Function ==
[https://www.uniprot.org/uniprot/SHOC2_HUMAN SHOC2_HUMAN] Core component of the SHOC2-MRAS-PP1c (SMP) holophosphatase complex that regulates activation of the MAPK pathway (PubMed:10783161, PubMed:16630891, PubMed:25137548, PubMed:35768504, PubMed:35830882, PubMed:35831509, PubMed:36175670). Acts as a scaffolding protein in the SMP complex (PubMed:35768504, PubMed:35830882, PubMed:35831509, PubMed:36175670). The SMP complex specifically dephosphorylates the inhibitory phosphorylation at 'Ser-259' of RAF1 kinase, 'Ser-365' of BRAF kinase and 'Ser-214' of ARAF kinase, stimulating their kinase activities (PubMed:10783161, PubMed:16630891, PubMed:35768504, PubMed:35830882, PubMed:35831509, PubMed:36175670). The SMP complex enhances the dephosphorylation activity and substrate specificity of PP1c (PubMed:35768504, PubMed:36175670).<ref>PMID:10783161</ref> <ref>PMID:16630891</ref> <ref>PMID:25137548</ref> <ref>PMID:35768504</ref> <ref>PMID:35830882</ref> <ref>PMID:35831509</ref> <ref>PMID:36175670</ref>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.


Authors: Finci, L.I., Bonsor, D.A., Simanshu, D.K.
Structure of SHOC2-KRAS-PP1C complex reveals RAS isoform-specific determinants and insights into targeting complex assembly by RAS inhibitors.,Bonsor DA, Finci LI, Potter JR, Young LC, Wall VE, Goldstein de Salazar R, Geis KR, Stephens T, Finney J, Nissley DV, McCormick F, Simanshu DK Nat Commun. 2026 Jan 10. doi: 10.1038/s41467-026-68319-1. PMID:41519889<ref>PMID:41519889</ref>


Description: Cryo-EM structure of SHOC2-KRAS-PP1CA (SKP) complex
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
[[Category: Finci, L.I]]
<div class="pdbe-citations 9o65" style="background-color:#fffaf0;"></div>
[[Category: Bonsor, D.A]]
== References ==
[[Category: Simanshu, D.K]]
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Bonsor DA]]
[[Category: Finci LI]]
[[Category: Simanshu DK]]
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