View source for 4iea


==14-3-3 isoform sigma in complex with a phosphorylated C-RAF peptide==
<StructureSection load='4iea' size='340' side='right'caption='[[4iea]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4iea]] is a 2 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=4IEA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4IEA 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]] 1.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</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=4iea FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4iea OCA], [https://pdbe.org/4iea PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4iea RCSB], [https://www.ebi.ac.uk/pdbsum/4iea PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4iea ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/1433S_HUMAN 1433S_HUMAN] Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. When bound to KRT17, regulates protein synthesis and epithelial cell growth by stimulating Akt/mTOR pathway (By similarity).  p53-regulated inhibitor of G2/M progression.
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== Publication Abstract from PubMed ==
One-third of all human cancers harbor somatic RAS mutations. This leads to aberrant activation of downstream signaling pathways involving the RAF kinases. Current ATP-competitive RAF inhibitors are active in cancers with somatic RAF mutations, such as BRAF(V600) mutant melanomas. However, they paradoxically promote the growth of RAS mutant tumors, partly due to the complex interplay between different homo- and heterodimers of A-RAF, B-RAF, and C-RAF. Based on pathway analysis and structure-guided compound identification, we describe the natural product cotylenin-A (CN-A) as stabilizer of the physical interaction of C-RAF with 14-3-3 proteins. CN-A binds to inhibitory 14-3-3 interaction sites of C-RAF, pSer233, and pSer259, but not to the activating interaction site, pSer621. While CN-A alone is inactive in RAS mutant cancer models, combined treatment with CN-A and an anti-EGFR antibody synergistically suppresses tumor growth in vitro and in vivo. This defines a novel pharmacologic strategy for treatment of RAS mutant cancers.

Stabilization of Physical RAF/14-3-3 Interaction by Cotylenin A as Treatment Strategy for RAS Mutant Cancers.,Molzan M, Kasper S, Roglin L, Skwarczynska M, Sassa T, Inoue T, Breitenbuecher F, Ohkanda J, Kato N, Schuler M, Ottmann C ACS Chem Biol. 2013 Sep 20;8(9):1869-75. doi: 10.1021/cb4003464. Epub 2013 Jul 5. PMID:23808890<ref>PMID:23808890</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 4iea" style="background-color:#fffaf0;"></div>

==See Also==
*[[14-3-3 protein 3D structures|14-3-3 protein 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Molzan M]]
[[Category: Ottmann C]]