View source for 5aqp


==Fragment-based screening of HSP70 sheds light on the functional role of ATP-binding site residues==
<StructureSection load='5aqp' size='340' side='right'caption='[[5aqp]], [[Resolution|resolution]] 2.08&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5aqp]] is a 6 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=5AQP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5AQP 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]] 2.08&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1LQ:QUINAZOLIN-4-AMINE'>1LQ</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</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=5aqp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aqp OCA], [https://pdbe.org/5aqp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5aqp RCSB], [https://www.ebi.ac.uk/pdbsum/5aqp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5aqp ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/HSP7C_HUMAN HSP7C_HUMAN] Acts as a repressor of transcriptional activation. Inhibits the transcriptional coactivator activity of CITED1 on Smad-mediated transcription. Chaperone. Component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing. May have a scaffolding role in the spliceosome assembly as it contacts all other components of the core complex.<ref>PMID:10722728</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The heat shock protein 70s (HSP70s) are molecular chaperones implicated in many cancers and of significant interest as targets for novel cancer therapies. Several HSP70 inhibitors have been reported, but because the majority have poor physicochemical properties and for many the exact mode of action is poorly understood, more detailed mechanistic and structural insight into ligand-binding to HSP70s is urgently needed. Here we describe the first comprehensive fragment-based inhibitor exploration of an HSP70 enzyme, which yielded an amino-quinazoline fragment that was elaborated to a novel ATP binding site ligand with different physicochemical properties to known adenosine-based HSP70 inhibitors. Crystal structures of amino-quinazoline ligands bound to the different conformational states of the HSP70 nucleotide binding domain highlighted the challenges of a fragment-based approach when applied to this particular flexible enzyme class with an ATP-binding site that changes shape and size during its catalytic cycle. In these studies we showed that Ser275 is a key residue in the selective binding of ATP. Additionally, the structural data revealed a potential functional role for the ATP ribose moiety in priming the protein for the formation of the ATP-bound pre-hydrolysis complex by influencing the conformation of one of the phosphate binding loops.

A fragment-based approach applied to a highly flexible target: Insights and challenges towards the inhibition of HSP70 isoforms.,Jones AM, Westwood IM, Osborne JD, Matthews TP, Cheeseman MD, Rowlands MG, Jeganathan F, Burke R, Lee D, Kadi N, Liu M, Richards M, McAndrew C, Yahya N, Dobson SE, Jones K, Workman P, Collins I, van Montfort RL Sci Rep. 2016 Oct 6;6:34701. doi: 10.1038/srep34701. PMID:27708405<ref>PMID:27708405</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5aqp" style="background-color:#fffaf0;"></div>

==See Also==
*[[Heat Shock Protein structures|Heat Shock Protein structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Burke R]]
[[Category: Cheeseman MD]]
[[Category: Collins I]]
[[Category: Dobson SE]]
[[Category: Jeganathan F]]
[[Category: Jones AM]]
[[Category: Jones K]]
[[Category: Kadi N]]
[[Category: Lee D]]
[[Category: Liu M]]
[[Category: Matthews TP]]
[[Category: McAndrew C]]
[[Category: Osborne JD]]
[[Category: Richards M]]
[[Category: Rowlands MG]]
[[Category: Westwood IM]]
[[Category: Workman P]]
[[Category: Yahya N]]
[[Category: Van Montfort RLM]]