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| | <StructureSection load='2vw5' size='340' side='right'caption='[[2vw5]], [[Resolution|resolution]] 1.90Å' scene=''> | | <StructureSection load='2vw5' size='340' side='right'caption='[[2vw5]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2vw5]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Atcc_18824 Atcc 18824]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VW5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VW5 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2vw5]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VW5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VW5 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BC6:(4E,8S,9R,10E,12S,13R,14S,16R)-13,20-DIHYDROXY-14-METHOXY-4,8,10,12,16-PENTAMETHYL-3-OXO-2-AZABICYCLO[16.3.1]DOCOSA-1(22),4,10,18,20-PENTAEN-9-YL+CARBAMATE'>BC6</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.9Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1hk7|1hk7]], [[1a4h|1a4h]], [[1us7|1us7]], [[2bre|2bre]], [[2cg9|2cg9]], [[1ah6|1ah6]], [[1usv|1usv]], [[1bgq|1bgq]], [[2iws|2iws]], [[1amw|1amw]], [[2brc|2brc]], [[1zwh|1zwh]], [[1usu|1usu]], [[1ah8|1ah8]], [[2cgf|2cgf]], [[2iwu|2iwu]], [[1am1|1am1]], [[2vls|2vls]], [[2iwx|2iwx]], [[2cge|2cge]], [[1zw9|1zw9]], [[2akp|2akp]]</div></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BC6:(4E,8S,9R,10E,12S,13R,14S,16R)-13,20-DIHYDROXY-14-METHOXY-4,8,10,12,16-PENTAMETHYL-3-OXO-2-AZABICYCLO[16.3.1]DOCOSA-1(22),4,10,18,20-PENTAEN-9-YL+CARBAMATE'>BC6</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=2vw5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vw5 OCA], [https://pdbe.org/2vw5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2vw5 RCSB], [https://www.ebi.ac.uk/pdbsum/2vw5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2vw5 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=2vw5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vw5 OCA], [https://pdbe.org/2vw5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2vw5 RCSB], [https://www.ebi.ac.uk/pdbsum/2vw5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2vw5 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/HSP82_YEAST HSP82_YEAST]] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. The nucleotide-free form of the dimer is found in an open conformation in which the N-termini are not dimerized and the complex is ready for client protein binding. Binding of ATP induces large conformational changes, resulting in the formation of a ring-like closed structure in which the N-terminal domains associate intramolecularly with the middle domain and also dimerize with each other, stimulating their intrinsic ATPase activity and acting as a clamp on the substrate. Finally, ATP hydrolysis results in the release of the substrate. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function. Required for growth at high temperatures.<ref>PMID:17114002</ref>
| + | [https://www.uniprot.org/uniprot/HSP82_YEAST HSP82_YEAST] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. The nucleotide-free form of the dimer is found in an open conformation in which the N-termini are not dimerized and the complex is ready for client protein binding. Binding of ATP induces large conformational changes, resulting in the formation of a ring-like closed structure in which the N-terminal domains associate intramolecularly with the middle domain and also dimerize with each other, stimulating their intrinsic ATPase activity and acting as a clamp on the substrate. Finally, ATP hydrolysis results in the release of the substrate. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function. Required for growth at high temperatures.<ref>PMID:17114002</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Atcc 18824]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Pearl, L H]] | + | [[Category: Saccharomyces cerevisiae]] |
| - | [[Category: Prodromou, C]] | + | [[Category: Pearl LH]] |
| - | [[Category: Roe, S M]] | + | [[Category: Prodromou C]] |
| - | [[Category: Atp-binding]] | + | [[Category: Roe SM]] |
| - | [[Category: Atpase]]
| + | |
| - | [[Category: Chaperone]]
| + | |
| - | [[Category: Cytoplasm]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Nucleotide-binding]]
| + | |
| - | [[Category: Stress response]]
| + | |
| Structural highlights
Function
HSP82_YEAST Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. The nucleotide-free form of the dimer is found in an open conformation in which the N-termini are not dimerized and the complex is ready for client protein binding. Binding of ATP induces large conformational changes, resulting in the formation of a ring-like closed structure in which the N-terminal domains associate intramolecularly with the middle domain and also dimerize with each other, stimulating their intrinsic ATPase activity and acting as a clamp on the substrate. Finally, ATP hydrolysis results in the release of the substrate. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function. Required for growth at high temperatures.[1]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
A biosynthetic medicinal chemistry approach was applied to the optimization of the natural product Hsp90 inhibitor macbecin. By genetic engineering, mutants have been created to produce novel macbecin analogues including a nonquinone compound (5) that has significantly improved binding affinity to Hsp90 (Kd 3 nM vs 240 nM for macbecin) and reduced toxicity (MTD > or = 250 mg/kg). Structural flexibility may contribute to the preorganization of 5 to exist in solution in the Hsp90-bound conformation.
Optimizing natural products by biosynthetic engineering: discovery of nonquinone Hsp90 inhibitors.,Zhang MQ, Gaisser S, Nur-E-Alam M, Sheehan LS, Vousden WA, Gaitatzis N, Peck G, Coates NJ, Moss SJ, Radzom M, Foster TA, Sheridan RM, Gregory MA, Roe SM, Prodromou C, Pearl L, Boyd SM, Wilkinson B, Martin CJ J Med Chem. 2008 Sep 25;51(18):5494-7. PMID:18800759[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Proisy N, Sharp SY, Boxall K, Connelly S, Roe SM, Prodromou C, Slawin AM, Pearl LH, Workman P, Moody CJ. Inhibition of Hsp90 with synthetic macrolactones: synthesis and structural and biological evaluation of ring and conformational analogs of radicicol. Chem Biol. 2006 Nov;13(11):1203-15. PMID:17114002 doi:10.1016/j.chembiol.2006.09.015
- ↑ Zhang MQ, Gaisser S, Nur-E-Alam M, Sheehan LS, Vousden WA, Gaitatzis N, Peck G, Coates NJ, Moss SJ, Radzom M, Foster TA, Sheridan RM, Gregory MA, Roe SM, Prodromou C, Pearl L, Boyd SM, Wilkinson B, Martin CJ. Optimizing natural products by biosynthetic engineering: discovery of nonquinone Hsp90 inhibitors. J Med Chem. 2008 Sep 25;51(18):5494-7. PMID:18800759 doi:10.1021/jm8006068
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