2wi5: Difference between revisions
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< | ==Orally Active 2-Amino Thienopyrimidine Inhibitors of the Hsp90 Chaperone== | ||
<StructureSection load='2wi5' size='340' side='right'caption='[[2wi5]], [[Resolution|resolution]] 2.10Å' scene=''> | |||
You may | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2wi5]] 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=2WI5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2WI5 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1Å</td></tr> | |||
-- | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZZ5:3,6-DIAMINO-5-CYANO-4-(4-ETHOXYPHENYL)THIENO[2,3-B]PYRIDINE-2-CARBOXAMIDE'>ZZ5</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=2wi5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wi5 OCA], [https://pdbe.org/2wi5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2wi5 RCSB], [https://www.ebi.ac.uk/pdbsum/2wi5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2wi5 ProSAT]</span></td></tr> | |||
</table> | |||
== 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 == | |||
[[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/wi/2wi5_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/main_output.php?pdb_ID=2wi5 ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe novel 2-aminothieno[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors, which were designed by combining structural elements of distinct low affinity hits generated from fragment-based and in silico screening exercises in concert with structural information from X-ray protein crystallography. Examples from this series have high affinity (IC(50) = 50-100 nM) for Hsp90 as measured in a fluorescence polarization (FP) competitive binding assay and are active in human cancer cell lines where they inhibit cell proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Several examples (34a, 34d and 34i) caused tumor growth regression at well tolerated doses when administered orally in a human BT474 human breast cancer xenograft model. | |||
Combining Hit Identification Strategies: Fragment-Based and in Silico Approaches to Orally Active 2-Aminothieno[2,3-d]pyrimidine Inhibitors of the Hsp90 Molecular Chaperone.,Brough PA, Barril X, Borgognoni J, Chene P, Davies NG, Davis B, Drysdale MJ, Dymock B, Eccles SA, Garcia-Echeverria C, Fromont C, Hayes A, Hubbard RE, Jordan AM, Jensen MR, Massey A, Merrett A, Padfield A, Parsons R, Radimerski T, Raynaud FI, Robertson A, Roughley SD, Schoepfer J, Simmonite H, Sharp SY, Surgenor A, Valenti M, Walls S, Webb P, Wood M, Workman P, Wright L J Med Chem. 2009 Jul 17. PMID:19610616<ref>PMID:19610616</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2wi5" style="background-color:#fffaf0;"></div> | |||
== | |||
==See Also== | ==See Also== | ||
*[[Heat Shock | *[[Heat Shock Protein structures|Heat Shock Protein structures]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Barril | [[Category: Large Structures]] | ||
[[Category: Borgognoni | [[Category: Barril X]] | ||
[[Category: Brough | [[Category: Borgognoni J]] | ||
[[Category: Chene | [[Category: Brough PA]] | ||
[[Category: Davies | [[Category: Chene P]] | ||
[[Category: Davis | [[Category: Davies NGM]] | ||
[[Category: Drysdale | [[Category: Davis B]] | ||
[[Category: Dymock | [[Category: Drysdale MJ]] | ||
[[Category: Eccles | [[Category: Dymock B]] | ||
[[Category: Fromont | [[Category: Eccles SA]] | ||
[[Category: Garcia-Echeverria | [[Category: Fromont C]] | ||
[[Category: Hayes | [[Category: Garcia-Echeverria C]] | ||
[[Category: Hubbard | [[Category: Hayes A]] | ||
[[Category: Jordan | [[Category: Hubbard RE]] | ||
[[Category: Massey | [[Category: Jordan AM]] | ||
[[Category: Merret | [[Category: Massey A]] | ||
[[Category: Padfield | [[Category: Merret A]] | ||
[[Category: Parsons | [[Category: Padfield A]] | ||
[[Category: Radimerski | [[Category: Parsons R]] | ||
[[Category: Raynaud | [[Category: Radimerski T]] | ||
[[Category: Robertson | [[Category: Raynaud FI]] | ||
[[Category: Roughley | [[Category: Robertson A]] | ||
[[Category: Rugaard-Jensen | [[Category: Roughley SD]] | ||
[[Category: Schoepfer | [[Category: Rugaard-Jensen M]] | ||
[[Category: Simmonite | [[Category: Schoepfer J]] | ||
[[Category: Surgenor | [[Category: Simmonite H]] | ||
[[Category: Valenti | [[Category: Surgenor A]] | ||
[[Category: Walls | [[Category: Valenti M]] | ||
[[Category: Webb | [[Category: Walls S]] | ||
[[Category: Wood | [[Category: Webb P]] | ||
[[Category: Workman | [[Category: Wood M]] | ||
[[Category: Wright | [[Category: Workman P]] | ||
[[Category: Wright LM]] | |||