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| | <StructureSection load='2xab' size='340' side='right'caption='[[2xab]], [[Resolution|resolution]] 1.90Å' scene=''> | | <StructureSection load='2xab' size='340' side='right'caption='[[2xab]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2xab]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2XAB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2XAB FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2xab]] is a 2 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=2XAB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2XAB FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=VHD:4-(1,3-DIHYDRO-2H-ISOINDOL-2-YLCARBONYL)-6-(1-METHYLETHYL)BENZENE-1,3-DIOL'>VHD</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;'>[[2cdd|2cdd]], [[1yes|1yes]], [[1uy9|1uy9]], [[1byq|1byq]], [[2bsm|2bsm]], [[1osf|1osf]], [[2wi3|2wi3]], [[1uy8|1uy8]], [[2bug|2bug]], [[2wi4|2wi4]], [[2uwd|2uwd]], [[2wi7|2wi7]], [[2bt0|2bt0]], [[1yer|1yer]], [[1uyg|1uyg]], [[2bz5|2bz5]], [[2ccu|2ccu]], [[2ccs|2ccs]], [[1uyi|1uyi]], [[1yc3|1yc3]], [[1uyf|1uyf]], [[1uyd|1uyd]], [[2byi|2byi]], [[2wi2|2wi2]], [[1uy6|1uy6]], [[2vci|2vci]], [[2wi1|2wi1]], [[2vcj|2vcj]], [[1yc4|1yc4]], [[2fwz|2fwz]], [[2c2l|2c2l]], [[1uyk|1uyk]], [[1uyh|1uyh]], [[2cct|2cct]], [[2fwy|2fwy]], [[1uye|1uye]], [[1uyl|1uyl]], [[2wi6|2wi6]], [[1yc1|1yc1]], [[1uyc|1uyc]], [[1uy7|1uy7]], [[1yet|1yet]], [[2jjc|2jjc]], [[2byh|2byh]], [[2wi5|2wi5]]</div></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=VHD:4-(1,3-DIHYDRO-2H-ISOINDOL-2-YLCARBONYL)-6-(1-METHYLETHYL)BENZENE-1,3-DIOL'>VHD</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=2xab FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xab OCA], [https://pdbe.org/2xab PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2xab RCSB], [https://www.ebi.ac.uk/pdbsum/2xab PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2xab 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=2xab FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xab OCA], [https://pdbe.org/2xab PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2xab RCSB], [https://www.ebi.ac.uk/pdbsum/2xab PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2xab ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/HS90A_HUMAN HS90A_HUMAN]] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. 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.<ref>PMID:15937123</ref> <ref>PMID:11274138</ref>
| + | [https://www.uniprot.org/uniprot/HS90A_HUMAN HS90A_HUMAN] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. 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.<ref>PMID:15937123</ref> <ref>PMID:11274138</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: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Brian, M A.O]]
| + | [[Category: Callaghan O]] |
| - | [[Category: Callaghan, O]] | + | [[Category: Carr MG]] |
| - | [[Category: Carr, M G]] | + | [[Category: Chessari G]] |
| - | [[Category: Chessari, G]] | + | [[Category: Congreve m]] |
| - | [[Category: Congreve, m]] | + | [[Category: Cowan S]] |
| - | [[Category: Cowan, S]] | + | [[Category: Coyle JE]] |
| - | [[Category: Coyle, J E]] | + | [[Category: Downham R]] |
| - | [[Category: Downham, R]] | + | [[Category: Figueroa E]] |
| - | [[Category: Figueroa, E]] | + | [[Category: Frederickson M]] |
| - | [[Category: Frederickson, M]] | + | [[Category: Graham B]] |
| - | [[Category: Graham, B]] | + | [[Category: McMenamin R]] |
| - | [[Category: McMenamin, R]] | + | [[Category: Murray CW]] |
| - | [[Category: Murray, C W]] | + | [[Category: O'Brian MA]] |
| - | [[Category: Patel, S]] | + | [[Category: Patel S]] |
| - | [[Category: Phillips, T R]] | + | [[Category: Phillips TR]] |
| - | [[Category: Williams, G]] | + | [[Category: Williams G]] |
| - | [[Category: Woodhead, A J]] | + | [[Category: Woodhead AJ]] |
| - | [[Category: Woolford, A J.A]] | + | [[Category: Woolford AJA]] |
| - | [[Category: Atp-binding]]
| + | |
| - | [[Category: Cancer]]
| + | |
| - | [[Category: Chaperone]]
| + | |
| - | [[Category: Nucleotide-binding]]
| + | |
| - | [[Category: Stress response]]
| + | |
| Structural highlights
Function
HS90A_HUMAN Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. 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.[1] [2]
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
Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) are currently generating significant interest in clinical development as potential treatments for cancer. In a preceding publication (DOI: 10.1021/jm100059d ) we describe Astex's approach to screening fragments against Hsp90 and the subsequent optimization of two hits into leads with inhibitory activities in the low nanomolar range. This paper describes the structure guided optimization of the 2,4-dihydroxybenzamide lead molecule 1 and details some of the drug discovery strategies employed in the identification of AT13387 (35), which has progressed through preclinical development and is currently being tested in man.
Discovery of (2,4-Dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-di hydroisoindol-2-yl]methanone (AT13387), a Novel Inhibitor of the Molecular Chaperone Hsp90 by Fragment Based Drug Design.,Woodhead AJ, Angove H, Carr MG, Chessari G, Congreve M, Coyle JE, Cosme J, Graham B, Day PJ, Downham R, Fazal L, Feltell R, Figueroa E, Frederickson M, Lewis J, McMenamin R, Murray CW, O'Brien MA, Parra L, Patel S, Phillips T, Rees DC, Rich S, Smith DM, Trewartha G, Vinkovic M, Williams B, Woolford AJ J Med Chem. 2010 Jul 28. PMID:20662534[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Martinez-Ruiz A, Villanueva L, Gonzalez de Orduna C, Lopez-Ferrer D, Higueras MA, Tarin C, Rodriguez-Crespo I, Vazquez J, Lamas S. S-nitrosylation of Hsp90 promotes the inhibition of its ATPase and endothelial nitric oxide synthase regulatory activities. Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8525-30. Epub 2005 Jun 3. PMID:15937123 doi:10.1073/pnas.0407294102
- ↑ Forsythe HL, Jarvis JL, Turner JW, Elmore LW, Holt SE. Stable association of hsp90 and p23, but Not hsp70, with active human telomerase. J Biol Chem. 2001 May 11;276(19):15571-4. Epub 2001 Mar 23. PMID:11274138 doi:10.1074/jbc.C100055200
- ↑ Woodhead AJ, Angove H, Carr MG, Chessari G, Congreve M, Coyle JE, Cosme J, Graham B, Day PJ, Downham R, Fazal L, Feltell R, Figueroa E, Frederickson M, Lewis J, McMenamin R, Murray CW, O'Brien MA, Parra L, Patel S, Phillips T, Rees DC, Rich S, Smith DM, Trewartha G, Vinkovic M, Williams B, Woolford AJ. Discovery of (2,4-Dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-di hydroisoindol-2-yl]methanone (AT13387), a Novel Inhibitor of the Molecular Chaperone Hsp90 by Fragment Based Drug Design. J Med Chem. 2010 Jul 28. PMID:20662534 doi:10.1021/jm100060b
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