2fwy: Difference between revisions
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'''Structure of human Hsp90-alpha bound to the potent water soluble inhibitor PU-H64'''<br /> | '''Structure of human Hsp90-alpha bound to the potent water soluble inhibitor PU-H64'''<br /> | ||
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==About this Structure== | ==About this Structure== | ||
2FWY is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with H64 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | 2FWY is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=H64:'>H64</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2FWY OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: purine]] | [[Category: purine]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 17:26:27 2008'' | ||
Revision as of 15:26, 15 February 2008
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Structure of human Hsp90-alpha bound to the potent water soluble inhibitor PU-H64
Overview
Hsp90 chaperones play a critical role in modulating the activity of many, cell signaling proteins and are an attractive target for anti-cancer, therapeutics. We report here the structures of the water soluble, 8-aryl-sulfanyl adenine class Hsp90 inhibitors, 1 (PU-H71) and 2 (PU-H64), in complex with the N-terminal domain of human Hsp90alpha. The, conformation of 1 when bound to Hsp90 differs from previously reported, 8-aryl adenine Hsp90 inhibitors including 3 (PU24FCl). While the binding, mode for 3 places the 2'-halide of the 8-aryl group on top of the adenine, ring, for 1 and 2, we show that the 2'-halide is rotated approximately 180, degrees away. This difference explains the opposing trends in Hsp90, inhibitory activity for the 2'-halo derivatives of the 3',4',5'-trimethoxy, series where Cl > Br > I compared to the 4',5'-methylenedioxy series where, I > Br > Cl. We also present quantum chemical calculations of 2 and its, analogues that illuminate their basis for Hsp90 inhibition. The calculated, conformation of 2 agreed well with the crystallographically observed, conformations of 1 and 2. The predictive nature of the calculations has, allowed the exploration of additional derivatives based on the 8-aryl, adenine scaffold.
About this Structure
2FWY is a Single protein structure of sequence from Homo sapiens with H64 as ligand. Full crystallographic information is available from OCA.
Reference
Structural and quantum chemical studies of 8-aryl-sulfanyl adenine class Hsp90 inhibitors., Immormino RM, Kang Y, Chiosis G, Gewirth DT, J Med Chem. 2006 Aug 10;49(16):4953-60. PMID:16884307
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