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==Apo solution structure of Hop TPR2A==
==Apo solution structure of Hop TPR2A==
<StructureSection load='2nc9' size='340' side='right'caption='[[2nc9]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
<StructureSection load='2nc9' size='340' side='right'caption='[[2nc9]]' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[2nc9]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2NC9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2NC9 FirstGlance]. <br>
<table><tr><td colspan='2'>[[2nc9]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2NC9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2NC9 FirstGlance]. <br>
</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">STIP1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</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=2nc9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nc9 OCA], [https://pdbe.org/2nc9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2nc9 RCSB], [https://www.ebi.ac.uk/pdbsum/2nc9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2nc9 ProSAT]</span></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=2nc9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nc9 OCA], [https://pdbe.org/2nc9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2nc9 RCSB], [https://www.ebi.ac.uk/pdbsum/2nc9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2nc9 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[https://www.uniprot.org/uniprot/STIP1_HUMAN STIP1_HUMAN]] Mediates the association of the molecular chaperones HSC70 and HSP90 (HSPCA and HSPCB).  
[https://www.uniprot.org/uniprot/STIP1_HUMAN STIP1_HUMAN] Mediates the association of the molecular chaperones HSC70 and HSP90 (HSPCA and HSPCB).
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Heat shock protein 90 (Hsp90) is a molecular chaperone that plays an important role in tumour biology by promoting the stabilisation and activity of oncogenic 'client' proteins. Inhibition of Hsp90 by small-molecule drugs, acting via its ATP hydrolysis site, has shown promise as a molecularly targeted cancer therapy. Owing to the importance of Hop and other tetratricopeptide repeat (TPR)-containing cochaperones in regulating Hsp90 activity, the Hsp90-TPR domain interface is an alternative site for inhibitors, which could result in effects distinct from ATP site binders. The TPR binding site of Hsp90 cochaperones includes a shallow, positively charged groove that poses a significant challenge for druggability. Herein, we report the apo, solution-state structure of Hop TPR2A which enables this target for NMR-based screening approaches. We have designed prototype TPR ligands that mimic key native 'carboxylate clamp' interactions between Hsp90 and its TPR cochaperones and show that they block binding between Hop TPR2A and the Hsp90 C-terminal MEEVD peptide. We confirm direct TPR-binding of these ligands by mapping (1)H-(15)N HSQC chemical shift perturbations to our new NMR structure. Our work provides a novel structure, a thorough assessment of druggability and robust screening approaches that may offer a potential route, albeit difficult, to address the chemically challenging nature of the Hop TPR2A target, with relevance to other TPR domain interactors.
 
Solution structure of the Hop TPR2A domain and investigation of target druggability by NMR, biochemical and in silico approaches.,Darby JF, Vidler LR, Simpson PJ, Al-Lazikani B, Matthews SJ, Sharp SY, Pearl LH, Hoelder S, Workman P Sci Rep. 2020 Sep 29;10(1):16000. doi: 10.1038/s41598-020-71969-w. PMID:32994435<ref>PMID:32994435</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2nc9" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[HOP protein|HOP protein]]
*[[HOP protein|HOP protein]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Darby, J F]]
[[Category: Darby JF]]
[[Category: Hoelder, S]]
[[Category: Hoelder S]]
[[Category: Matthews, S J]]
[[Category: Matthews SJ]]
[[Category: Pearl, L H]]
[[Category: Pearl LH]]
[[Category: Sharp, S Y]]
[[Category: Sharp SY]]
[[Category: Simpson, P J]]
[[Category: Simpson PJ]]
[[Category: Vidler, L R]]
[[Category: Vidler LR]]
[[Category: Workman, P]]
[[Category: Workman P]]
[[Category: Chaperone]]
[[Category: Heat-shock]]
[[Category: Hsp90]]
[[Category: Tpr]]
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