2yjw: Difference between revisions
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== | ==Tricyclic series of Hsp90 inhibitors== | ||
<StructureSection load='2yjw' size='340' side='right' caption='[[2yjw]], [[Resolution|resolution]] 1.61Å' scene=''> | <StructureSection load='2yjw' size='340' side='right'caption='[[2yjw]], [[Resolution|resolution]] 1.61Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2yjw]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[2yjw]] 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=2YJW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2YJW 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]] 1.61Å</td></tr> | ||
<tr id=' | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=YJW:4-(5-METHYL-4-PHENYLISOXAZOL-3-YL)BENZENE-1,3-DIOL'>YJW</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2yjw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2yjw OCA], [https://pdbe.org/2yjw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2yjw RCSB], [https://www.ebi.ac.uk/pdbsum/2yjw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2yjw 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> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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==See Also== | ==See Also== | ||
*[[Heat Shock | *[[Heat Shock Protein structures|Heat Shock Protein structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Dupuy A]] | ||
[[Category: | [[Category: Vallee F]] | ||
Latest revision as of 17:05, 1 February 2024
Tricyclic series of Hsp90 inhibitorsTricyclic series of Hsp90 inhibitors
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] Publication Abstract from PubMedA novel class of heat shock protein 90 (Hsp90) inhibitors was developed after a low throughput screen (LTS) of a focused library containing approximately 21K compounds selected by virtual screening. The initial [1-{3-H-imidazo[4-5-c]pyridin-2-yl}-3,4-dihydro-2H-pyrido[2,1-a]isoindole- 6-one] (1) compound showed moderate activity (IC(50) = 7.6 muM on Hsp82, the yeast homologue of Hsp90). A high-resolution X-ray structure shows that compound 1 binds into an "induced" hydrophobic pocket, 10-15 A away from the ATP/resorcinol binding site. Iterative cycles of structure-based drug design (SBDD) and chemical synthesis led to the design and preparation of analogues with improved affinity. These optimized molecules make productive interactions within the ATP binding site as reported by other Hsp90 inhibitors. This resulted in compound 8, which is a highly potent inhibitor in biochemical and cellular assays (K(d) = 0.35 nM on Hsp90; IC(50) = 30 nM on SKBr3 mammary carcinoma cells) and in an in vivo leukemia model. Tricyclic Series of Heat Shock Protein 90 (Hsp90) Inhibitors Part I: Discovery of Tricyclic Imidazo[4,5-c]pyridines as Potent Inhibitors of the Hsp90 Molecular Chaperone.,Vallee F, Carrez C, Pilorge F, Dupuy A, Parent A, Bertin L, Thompson F, Ferrari P, Fassy F, Lamberton A, Thomas A, Arrebola R, Guerif S, Rohaut A, Certal V, Ruxer JM, Delorme C, Jouanen A, Dumas J, Grepin C, Combeau C, Goulaouic H, Dereu N, Mikol V, Mailliet P, Minoux H J Med Chem. 2011 Oct 27;54(20):7206-19. Epub 2011 Oct 5. PMID:21972823[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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