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| | ==HSP72 with adenosine-derived inhibitor== | | ==HSP72 with adenosine-derived inhibitor== |
| - | <StructureSection load='5aqz' size='340' side='right' caption='[[5aqz]], [[Resolution|resolution]] 1.65Å' scene=''> | + | <StructureSection load='5aqz' size='340' side='right'caption='[[5aqz]], [[Resolution|resolution]] 1.65Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5aqz]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AQZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AQZ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5aqz]] 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=5AQZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5AQZ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SGV:SANGIVAMYCIN'>SGV</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.65Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5aqf|5aqf]], [[5aqg|5aqg]], [[5aqh|5aqh]], [[5aqi|5aqi]], [[5aqj|5aqj]], [[5aqk|5aqk]], [[5aql|5aql]], [[5aqm|5aqm]], [[5aqn|5aqn]], [[5aqo|5aqo]], [[5aqp|5aqp]], [[5aqq|5aqq]], [[5aqr|5aqr]], [[5aqs|5aqs]], [[5aqt|5aqt]], [[5aqu|5aqu]], [[5aqv|5aqv]], [[5aqw|5aqw]], [[5aqx|5aqx]], [[5aqy|5aqy]], [[5ar0|5ar0]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SGV:SANGIVAMYCIN'>SGV</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mitochondrial_protein-transporting_ATPase Mitochondrial protein-transporting ATPase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.3.51 3.6.3.51] </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=5aqz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aqz OCA], [https://pdbe.org/5aqz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5aqz RCSB], [https://www.ebi.ac.uk/pdbsum/5aqz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5aqz ProSAT]</span></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=5aqz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aqz OCA], [http://pdbe.org/5aqz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5aqz RCSB], [http://www.ebi.ac.uk/pdbsum/5aqz PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5aqz" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5aqz" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Heat Shock Protein structures|Heat Shock Protein structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Mitochondrial protein-transporting ATPase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Barbeau, O]] | + | [[Category: Large Structures]] |
| - | [[Category: Burke, R]] | + | [[Category: Barbeau O]] |
| - | [[Category: Cheeseman, M D]] | + | [[Category: Burke R]] |
| - | [[Category: Collins, I]] | + | [[Category: Cheeseman MD]] |
| - | [[Category: Dobson, S E]] | + | [[Category: Collins I]] |
| - | [[Category: Jeganathan, F]] | + | [[Category: Dobson SE]] |
| - | [[Category: Jones, A M]] | + | [[Category: Jeganathan F]] |
| - | [[Category: Jones, K]] | + | [[Category: Jones AM]] |
| - | [[Category: Montfort, R L.M van]]
| + | [[Category: Jones K]] |
| - | [[Category: Rowlands, M G]] | + | [[Category: Rowlands MG]] |
| - | [[Category: Westwood, I M]] | + | [[Category: Westwood IM]] |
| - | [[Category: Workman, P]] | + | [[Category: Workman P]] |
| - | [[Category: Adenosine]] | + | [[Category: Van Montfort RLM]] |
| - | [[Category: Atpase]]
| + | |
| - | [[Category: Chaperone]]
| + | |
| - | [[Category: Heat shock protein]]
| + | |
| - | [[Category: Hsp70]]
| + | |
| - | [[Category: Hsp72]]
| + | |
| - | [[Category: Inhibitor]]
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| Structural highlights
Function
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).[1] [2] [3]
Publication Abstract from PubMed
HSP70 is a molecular chaperone and a key component of the heat-shock response. Because of its proposed importance in oncology, this protein has become a popular target for drug discovery, efforts which have as yet brought little success. This study demonstrates that adenosine-derived HSP70 inhibitors potentially bind to the protein with a novel mechanism of action, the stabilization by desolvation of an intramolecular salt-bridge which induces a conformational change in the protein, leading to high affinity ligands. We also demonstrate that through the application of this mechanism, adenosine-derived HSP70 inhibitors can be optimized in a rational manner.
Exploiting Protein Conformational Change to Optimize Adenosine-Derived Inhibitors of HSP70.,Cheeseman MD, Westwood IM, Barbeau O, Rowlands M, Dobson S, Jones AM, Jeganathan F, Burke R, Kadi N, Workman P, Collins I, van Montfort RL, Jones K J Med Chem. 2016 May 11. PMID:27119979[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Perez-Vargas J, Romero P, Lopez S, Arias CF. The peptide-binding and ATPase domains of recombinant hsc70 are required to interact with rotavirus and reduce its infectivity. J Virol. 2006 Apr;80(7):3322-31. PMID:16537599 doi:http://dx.doi.org/80/7/3322
- ↑ Liu X, Liu D, Qian D, Dai J, An Y, Jiang S, Stanley B, Yang J, Wang B, Liu X, Liu DX. Nucleophosmin (NPM1/B23) interacts with activating transcription factor 5 (ATF5) protein and promotes proteasome- and caspase-dependent ATF5 degradation in hepatocellular carcinoma cells. J Biol Chem. 2012 Jun 1;287(23):19599-609. doi: 10.1074/jbc.M112.363622. Epub, 2012 Apr 23. PMID:22528486 doi:http://dx.doi.org/10.1074/jbc.M112.363622
- ↑ Chen Z, Barbi J, Bu S, Yang HY, Li Z, Gao Y, Jinasena D, Fu J, Lin F, Chen C, Zhang J, Yu N, Li X, Shan Z, Nie J, Gao Z, Tian H, Li Y, Yao Z, Zheng Y, Park BV, Pan Z, Zhang J, Dang E, Li Z, Wang H, Luo W, Li L, Semenza GL, Zheng SG, Loser K, Tsun A, Greene MI, Pardoll DM, Pan F, Li B. The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3. Immunity. 2013 Aug 22;39(2):272-85. doi: 10.1016/j.immuni.2013.08.006. PMID:23973223 doi:http://dx.doi.org/10.1016/j.immuni.2013.08.006
- ↑ Cheeseman MD, Westwood IM, Barbeau O, Rowlands M, Dobson S, Jones AM, Jeganathan F, Burke R, Kadi N, Workman P, Collins I, van Montfort RL, Jones K. Exploiting Protein Conformational Change to Optimize Adenosine-Derived Inhibitors of HSP70. J Med Chem. 2016 May 11. PMID:27119979 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b02001
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