View source for 6ghp


==14-3-3sigma in complex with a TASK3 peptide stabilized by semi-synthetic natural product FC-NAc==
<StructureSection load='6ghp' size='340' side='right' caption='[[6ghp]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6ghp]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GHP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GHP FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EZ5:~{N}-[(2~{S})-2-[(1~{E},3~{R},4~{S},8~{R},9~{R},10~{R},11~{S},14~{S})-14-(methoxymethyl)-3,10-dimethyl-8-[(2~{S},3~{R},4~{S},5~{S},6~{R})-6-(2-methylbut-3-en-2-yloxymethyl)-3,4,5-tris(oxidanyl)oxan-2-yl]oxy-4,9-bis(oxidanyl)-6-tricyclo[9.3.0.0^{3,7}]tetradeca-1,6-dienyl]propyl]ethanamide'>EZ5</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=CSO:S-HYDROXYCYSTEINE'>CSO</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SFN, HME1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ghp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ghp OCA], [http://pdbe.org/6ghp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ghp RCSB], [http://www.ebi.ac.uk/pdbsum/6ghp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ghp ProSAT]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/KCNK9_HUMAN KCNK9_HUMAN]] Intellectual deficit, Birk-Barel type. Birk-Barel mental retardation dysmorphism syndrome (BIBAS) [MIM:[http://omim.org/entry/612292 612292]]: A syndrome characterized by mental retardation, hypotonia, hyperactivity, and facial dysmorphism. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:18678320</ref>  
== Function ==
[[http://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. [[http://www.uniprot.org/uniprot/KCNK9_HUMAN KCNK9_HUMAN]] pH-dependent, voltage-insensitive, background potassium channel protein.<ref>PMID:11042359</ref> <ref>PMID:11431495</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The natural product family of fusicoccanes are stabilizers of 14-3-3 mediated protein-protein interactions (PPIs), some of which possess antitumor activity. In this study, we present the first use of molecular dynamics (MD) to rationally design PPI stabilizers with increased potency. Synthesis of a focused library, followed by characterization by fluorescence polarization, mutational studies and X-ray crystallography confirmed the power of the MD-based design approach, revealing the potential for an additional hydrogen bond with the 14-3-3 protein which significantly increased potency. Additionally, these compounds exert their action in a cellular environment with increased potency. The newly found polar interaction could provide an anchoring point for new small molecule PPI stabilizers. These results facilitate the development of fusicoccanes towards drugs or tool compounds, as well as allowing the study of the fundamental principles behind PPI stabilization.

Rationally Designed Semi-Synthetic Natural Product Analogues for Stabilization of 14-3-3 Protein-Protein Interactions.,Ottmann C, Andrei SA, de Vink P, Sijbesma E, Han L, Brunsveld L, Kato N, Higuchi Y Angew Chem Int Ed Engl. 2018 Jul 19. doi: 10.1002/anie.201806584. PMID:30025189<ref>PMID:30025189</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6ghp" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Andrei, S A]]
[[Category: Brunsveld, L]]
[[Category: Higuchi, Y]]
[[Category: Ottmann, C]]
[[Category: Vink, P J.de]]
[[Category: Natural product]]
[[Category: Potassium channel]]
[[Category: Ppi]]
[[Category: Signaling protein]]
[[Category: Stabilizer]]