2xdl: Difference between revisions

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-[[Image:2xdl.png|left|200px]]
+==STRUCTURE OF HSP90 WITH SMALL MOLECULE INHIBITOR BOUND==
+<StructureSection load='2xdl' size='340' side='right' caption='[[2xdl]], [[Resolution|resolution]] 1.98&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[2xdl]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2XDL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2XDL FirstGlance]. <br>
+</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2DL:2-METHYL-4-DIETHYLAMIDE-PHENOL'>2DL</scene><br>
+<tr><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]], [[2wi7|2wi7]], [[2bt0|2bt0]], [[1yer|1yer]], [[1uyg|1uyg]], [[2ccu|2ccu]], [[2bz5|2bz5]], [[2ccs|2ccs]], [[1uyf|1uyf]], [[1yc3|1yc3]], [[1uyi|1uyi]], [[1uyd|1uyd]], [[2byi|2byi]], [[2wi2|2wi2]], [[2vci|2vci]], [[1uy6|1uy6]], [[2wi1|2wi1]], [[2vcj|2vcj]], [[1yc4|1yc4]], [[2c2l|2c2l]], [[2fwz|2fwz]], [[1uyk|1uyk]], [[1uyh|1uyh]], [[2cct|2cct]], [[2fwy|2fwy]], [[1uye|1uye]], [[1uyl|1uyl]], [[2wi6|2wi6]], [[2xab|2xab]], [[1yc1|1yc1]], [[1uyc|1uyc]], [[1uy7|1uy7]], [[1yet|1yet]], [[2jjc|2jjc]], [[2byh|2byh]], [[2wi5|2wi5]], [[2xdk|2xdk]]</td></tr>
+<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2xdl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xdl OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2xdl RCSB], [http://www.ebi.ac.uk/pdbsum/2xdl PDBsum]</span></td></tr>
+<table>
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/xd/2xdl_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </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/chain_selection.php?pdb_ID=2ata ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Inhibitors 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.
-{{STRUCTURE_2xdl|  PDB=2xdl  |  SCENE=  }}
+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<ref>PMID:20718493</ref>
-===STRUCTURE OF HSP90 WITH SMALL MOLECULE INHIBITOR BOUND===
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
-{{ABSTRACT_PUBMED_20718493}}
-==About this Structure==
-[[2xdl]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2XDL OCA].
 ==See Also==
 *[[Heat Shock Proteins|Heat Shock Proteins]]
+== References ==
-==Reference==
+<references/>
-<ref group="xtra">PMID:020718493</ref><references group="xtra"/>
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
 [[Category: Callaghan, O.]]