|
|
| (One intermediate revision not shown.) |
| Line 3: |
Line 3: |
| | <StructureSection load='5mks' size='340' side='right'caption='[[5mks]], [[Resolution|resolution]] 1.99Å' scene=''> | | <StructureSection load='5mks' size='340' side='right'caption='[[5mks]], [[Resolution|resolution]] 1.99Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5mks]] is a 1 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=5MKS OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5MKS FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5mks]] 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=5MKS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MKS FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TI8:3-[(2~{R},3~{S},4~{R},5~{R})-5-[6-AZANYL-8-[(4-CHLOROPHENYL)METHYLAMINO]PURIN-9-YL]-3,4-BIS(OXIDANYL)OXOLAN-2-YL]PROPYL+PROP-2-ENOATE'>TI8</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]] 1.99Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HSPA1A, HSPA1, HSX70 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TI8:3-[(2~{R},3~{S},4~{R},5~{R})-5-[6-AZANYL-8-[(4-CHLOROPHENYL)METHYLAMINO]PURIN-9-YL]-3,4-BIS(OXIDANYL)OXOLAN-2-YL]PROPYL+PROP-2-ENOATE'>TI8</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5mks FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mks OCA], [http://pdbe.org/5mks PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mks RCSB], [http://www.ebi.ac.uk/pdbsum/5mks PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mks 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=5mks FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mks OCA], [https://pdbe.org/5mks PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5mks RCSB], [https://www.ebi.ac.uk/pdbsum/5mks PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5mks ProSAT]</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;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | The stress-inducible molecular chaperone, HSP72, is an important therapeutic target in oncology, but inhibiting this protein with small molecules has proven particularly challenging. Validating HSP72 inhibitors in cells is difficult owing to competition with the high affinity and abundance of its endogenous nucleotide substrates. We hypothesized this could be overcome using a cysteine-targeted irreversible inhibitor. Using rational design, we adapted a validated 8-N-benzyladenosine ligand for covalent bond formation and confirmed targeted irreversible inhibition. However, no cysteine in the protein was modified; instead, we demonstrate that lysine-56 is the key nucleophilic residue. Targeting this lysine could lead to a new design paradigm for HSP72 chemical probes and drugs.
| + | |
| - | | + | |
| - | An Irreversible Inhibitor of HSP72 that Unexpectedly Targets Lysine-56.,Pettinger J, Le Bihan YV, Widya M, van Montfort RL, Jones K, Cheeseman MD Angew Chem Int Ed Engl. 2017 Feb 22. doi: 10.1002/anie.201611907. PMID:28225177<ref>PMID:28225177</ref>
| + | |
| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 5mks" style="background-color:#fffaf0;"></div>
| + | |
| | | | |
| | ==See Also== | | ==See Also== |
| Line 26: |
Line 17: |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Bihan, Y V.Le]]
| + | [[Category: Cronin N]] |
| - | [[Category: Cronin, N]] | + | [[Category: Le Bihan Y-V]] |
| - | [[Category: Montfort, R L.M Van]] | + | [[Category: Pettinger J]] |
| - | [[Category: Pettinger, J]] | + | [[Category: Van Montfort RLM]] |
| - | [[Category: Westwood, I M]] | + | [[Category: Westwood IM]] |
| - | [[Category: Chaperone]] | + | |
| - | [[Category: Irreversible inhibitor]]
| + | |
| - | [[Category: Lysine modification]]
| + | |
| 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]
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
|
