2xdk: Difference between revisions
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<StructureSection load='2xdk' size='340' side='right'caption='[[2xdk]], [[Resolution|resolution]] 1.97Å' scene=''> | <StructureSection load='2xdk' size='340' side='right'caption='[[2xdk]], [[Resolution|resolution]] 1.97Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2xdk]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[2xdk]] 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=2XDK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2XDK FirstGlance]. <br> | ||
</td></tr><tr id=' | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.97Å</td></tr> | ||
<tr id=' | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=XDK:2-AMINO-4-PYRIDYL-PYRIMIDINE'>XDK</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=2xdk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xdk OCA], [https://pdbe.org/2xdk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2xdk RCSB], [https://www.ebi.ac.uk/pdbsum/2xdk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2xdk 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=2xdk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xdk OCA], [https://pdbe.org/2xdk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2xdk RCSB], [https://www.ebi.ac.uk/pdbsum/2xdk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2xdk 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> | |||
== 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: | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Callaghan | [[Category: Callaghan O]] | ||
[[Category: Carr | [[Category: Carr MG]] | ||
[[Category: Chessari | [[Category: Chessari G]] | ||
[[Category: Congreve | [[Category: Congreve M]] | ||
[[Category: Cowan | [[Category: Cowan S]] | ||
[[Category: Coyle | [[Category: Coyle JE]] | ||
[[Category: Downham | [[Category: Downham R]] | ||
[[Category: Figueroa | [[Category: Figueroa E]] | ||
[[Category: Frederickson | [[Category: Frederickson M]] | ||
[[Category: Graham | [[Category: Graham B]] | ||
[[Category: McMenamin | [[Category: McMenamin R]] | ||
[[Category: Murray | [[Category: Murray CW]] | ||
[[Category: OBrien | [[Category: OBrien MA]] | ||
[[Category: Patel | [[Category: Patel S]] | ||
[[Category: Phillips | [[Category: Phillips TR]] | ||
[[Category: Williams | [[Category: Williams G]] | ||
[[Category: Woodhead | [[Category: Woodhead AJ]] | ||
[[Category: Woolford | [[Category: Woolford AJA]] | ||
Latest revision as of 13:25, 9 May 2024
Structure of HSP90 with small molecule inhibitor boundStructure of HSP90 with small molecule inhibitor bound
Structural highlights
FunctionHS90A_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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