View source for 5aqx


==Fragment-based screening of HSP70 sheds light on the functional role of ATP-binding site residues==
<StructureSection load='5aqx' size='340' side='right'caption='[[5aqx]], [[Resolution|resolution]] 2.12&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5aqx]] is a 1 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=5AQX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5AQX 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]] 2.12&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=KC7:(1R,2S,3R,5R)-3-((5-(BENZYLOXY)QUINAZOLIN-4-YL)AMINO)-5-(HYDROXYMETHYL)CYCLOPENTANE-1,2-DIOL'>KC7</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=5aqx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aqx OCA], [https://pdbe.org/5aqx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5aqx RCSB], [https://www.ebi.ac.uk/pdbsum/5aqx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5aqx ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/HS71A_HUMAN HS71A_HUMAN] In cooperation with other chaperones, Hsp70s stabilize preexistent proteins against aggregation and mediate the folding of newly translated polypeptides in the cytosol as well as within organelles. These chaperones participate in all these processes through their ability to recognize nonnative conformations of other proteins. They bind extended peptide segments with a net hydrophobic character exposed by polypeptides during translation and membrane translocation, or following stress-induced damage. In case of rotavirus A infection, serves as a post-attachment receptor for the virus to facilitate entry into the cell. Essential for STUB1-mediated ubiquitination and degradation of FOXP3 in regulatory T-cells (Treg) during inflammation (PubMed:23973223).<ref>PMID:16537599</ref> <ref>PMID:22528486</ref> <ref>PMID:23973223</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 5aqx" 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]]