View source for 7jv1


==Crystal Structure of KSR1:MEK1 in complex with AMP-PNP, and allosteric MEK inhibitor APS-9-95-1==
<StructureSection load='7jv1' size='340' side='right'caption='[[7jv1]], [[Resolution|resolution]] 3.62&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7jv1]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Oryctolagus_cuniculus Oryctolagus cuniculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7JV1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JV1 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.62&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=VKG:3-cyclopropyl-5-[(2-fluoranyl-4-iodanyl-phenyl)amino]-6,8-dimethyl-1-[3-(methylsulfamoylamino)phenyl]pyrido[4,3-d]pyrimidine-2,4,7-trione'>VKG</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=7jv1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jv1 OCA], [https://pdbe.org/7jv1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7jv1 RCSB], [https://www.ebi.ac.uk/pdbsum/7jv1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7jv1 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/KSR1_HUMAN KSR1_HUMAN] Scaffolding protein that is part of a multiprotein signaling complex. Promotes phosphorylation of Raf family members and activation of downstream MAP kinases. Promotes activation of MAPK1 and/or MAPK3, both in response to EGF and to cAMP. Does not have kinase activity by itself.[UniProtKB:Q61097]
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== Publication Abstract from PubMed ==
The MAPK/ERK kinase MEK is a shared effector of the frequent cancer drivers KRAS and BRAF that has long been pursued as a drug target in oncology(1), and more recently in immunotherapy(2,3) and aging(4). However, many MEK inhibitors (MEKi) are limited due to on-target toxicities(5-7) and drug resistance(8-10). Accordingly, a molecular understanding of the structure and function of MEK within physiological complexes could provide a template for the design of safer and more effective therapies. Here we report X-ray crystal structures of MEK bound to the scaffold KSR (kinase suppressor of RAS) with various MEKi, including the clinical drug trametinib. The structures reveal an unexpected mode of binding in which trametinib directly engages KSR at the MEK interface. Through complexation, KSR remodels the prototypical MEKi allosteric pocket thereby impacting binding and kinetics, including drug residence time. Moreover, trametinib binds KSR-MEK but disrupts the related RAF-MEK complex through a mechanism that exploits evolutionarily conserved interface residues that distinguish these subcomplexes. Based on these insights we created trametiglue, which limits adaptive resistance to MEKi through enhanced interfacial binding. Together, our results reveal the plasticity of an interface pocket within MEK subcomplexes that has implications for the design of next-generation drugs targeting the RAS pathway.

Structural basis for the action of the drug trametinib at KSR-bound MEK.,Khan ZM, Real AM, Marsiglia WM, Chow A, Duffy ME, Yerabolu JR, Scopton AP, Dar AC Nature. 2020 Sep 14. pii: 10.1038/s41586-020-2760-4. doi:, 10.1038/s41586-020-2760-4. PMID:32927473<ref>PMID:32927473</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 7jv1" style="background-color:#fffaf0;"></div>

==See Also==
*[[Mitogen-activated protein kinase kinase 3D structures|Mitogen-activated protein kinase kinase 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Oryctolagus cuniculus]]
[[Category: Dar AC]]
[[Category: Khan ZM]]
[[Category: Scopton AP]]