2xk2: Difference between revisions
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==Structure of HSP90 with small molecule inhibitor bound== | ==Structure of HSP90 with small molecule inhibitor bound== | ||
<StructureSection load='2xk2' size='340' side='right' caption='[[2xk2]], [[Resolution|resolution]] 1.95Å' scene=''> | <StructureSection load='2xk2' size='340' side='right' caption='[[2xk2]], [[Resolution|resolution]] 1.95Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2xk2]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[2xk2]] 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=2XK2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2XK2 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2cdd|2cdd]], [[1yes|1yes]], [[1uy9|1uy9]], [[1byq|1byq]], [[2bsm|2bsm]], [[1osf|1osf]], [[2wi3|2wi3]], [[1uy8|1uy8]], [[2bug|2bug]], [[2wi4|2wi4]], [[2uwd|2uwd]], [[2xhx|2xhx]], [[2wi7|2wi7]], [[2bt0|2bt0]], [[1yer|1yer]], [[2xdu|2xdu]], [[1uyg|1uyg]], [[2bz5|2bz5]], [[2ccu|2ccu]], [[2xds|2xds]], [[2xdx|2xdx]], [[2ccs|2ccs]], [[1uyf|1uyf]], [[1yc3|1yc3]], [[1uyi|1uyi]], [[2xjj|2xjj]], [[1uyd|1uyd]], [[2byi|2byi]], [[2xdl|2xdl]], [[2wi2|2wi2]], [[2vci|2vci]], [[1uy6|1uy6]], [[2wi1|2wi1]], [[2vcj|2vcj]], [[1yc4|1yc4]], [[2xjx|2xjx]], [[2c2l|2c2l]], [[2fwz|2fwz]], [[2xdk|2xdk]], [[1uyh|1uyh]], [[2xjg|2xjg]], [[1uyk|1uyk]], [[2cct|2cct]], [[2fwy|2fwy]], [[1uyl|1uyl]], [[1uye|1uye]], [[2wi6|2wi6]], [[2xab|2xab]], [[1yc1|1yc1]], [[2xhr|2xhr]], [[2xht|2xht]], [[1uyc|1uyc]], [[1uy7|1uy7]], [[1yet|1yet]], [[2jjc|2jjc]], [[2byh|2byh]], [[2wi5|2wi5]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2cdd|2cdd]], [[1yes|1yes]], [[1uy9|1uy9]], [[1byq|1byq]], [[2bsm|2bsm]], [[1osf|1osf]], [[2wi3|2wi3]], [[1uy8|1uy8]], [[2bug|2bug]], [[2wi4|2wi4]], [[2uwd|2uwd]], [[2xhx|2xhx]], [[2wi7|2wi7]], [[2bt0|2bt0]], [[1yer|1yer]], [[2xdu|2xdu]], [[1uyg|1uyg]], [[2bz5|2bz5]], [[2ccu|2ccu]], [[2xds|2xds]], [[2xdx|2xdx]], [[2ccs|2ccs]], [[1uyf|1uyf]], [[1yc3|1yc3]], [[1uyi|1uyi]], [[2xjj|2xjj]], [[1uyd|1uyd]], [[2byi|2byi]], [[2xdl|2xdl]], [[2wi2|2wi2]], [[2vci|2vci]], [[1uy6|1uy6]], [[2wi1|2wi1]], [[2vcj|2vcj]], [[1yc4|1yc4]], [[2xjx|2xjx]], [[2c2l|2c2l]], [[2fwz|2fwz]], [[2xdk|2xdk]], [[1uyh|1uyh]], [[2xjg|2xjg]], [[1uyk|1uyk]], [[2cct|2cct]], [[2fwy|2fwy]], [[1uyl|1uyl]], [[1uye|1uye]], [[2wi6|2wi6]], [[2xab|2xab]], [[1yc1|1yc1]], [[2xhr|2xhr]], [[2xht|2xht]], [[1uyc|1uyc]], [[1uy7|1uy7]], [[1yet|1yet]], [[2jjc|2jjc]], [[2byh|2byh]], [[2wi5|2wi5]]</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=2xk2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xk2 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2xk2 RCSB], [http://www.ebi.ac.uk/pdbsum/2xk2 PDBsum]</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=2xk2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xk2 OCA], [http://pdbe.org/2xk2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2xk2 RCSB], [http://www.ebi.ac.uk/pdbsum/2xk2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2xk2 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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<text>to colour the structure by Evolutionary Conservation</text> | <text>to colour the structure by Evolutionary Conservation</text> | ||
</jmolCheckbox> | </jmolCheckbox> | ||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/ | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2xk2 ConSurf]. | ||
<div style="clear:both"></div> | <div style="clear:both"></div> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 2xk2" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Human]] | ||
[[Category: Callaghan, O]] | [[Category: Callaghan, O]] | ||
[[Category: Carr, M G]] | [[Category: Carr, M G]] | ||
Revision as of 22:32, 5 August 2016
Structure of HSP90 with small molecule inhibitor boundStructure of HSP90 with small molecule inhibitor bound
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 PubMedInhibitors of the chaperone Hsp90 are potentially useful as chemotherapeutic agents in cancer. This paper describes an application of fragment screening to Hsp90 using a combination of NMR and high throughput X-ray crystallography. The screening identified an aminopyrimidine with affinity in the high micromolar range and subsequent structure-based design allowed its optimization into a low nanomolar series with good ligand efficiency. A phenolic chemotype was also identified in fragment screening and was found to bind with affinity close to 1 mM. This fragment was optimized using structure based design into a resorcinol lead which has subnanomolar affinity for Hsp90, excellent cell potency, and good ligand efficiency. This fragment to lead campaign improved affinity for Hsp90 by over 1,000,000-fold with the addition of only six heavy atoms. The companion paper (DOI: 10.1021/jm100060b) describes how the resorcinol lead was optimized into a compound that is now in clinical trials for the treatment of cancer. Fragment-based drug discovery applied to hsp90. Discovery of two lead series with high ligand efficiency.,Murray CW, Carr MG, Callaghan O, Chessari G, Congreve M, Cowan S, Coyle JE, Downham R, Figueroa E, Frederickson M, Graham B, McMenamin R, O'Brien MA, Patel S, Phillips TR, Williams G, Woodhead AJ, Woolford AJ J Med Chem. 2010 Aug 26;53(16):5942-55. PMID:20718493[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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