2fwy
From Proteopedia
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[[Image:2fwy.jpg|left|200px]] | [[Image:2fwy.jpg|left|200px]] | ||
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'''Structure of human Hsp90-alpha bound to the potent water soluble inhibitor PU-H64''' | '''Structure of human Hsp90-alpha bound to the potent water soluble inhibitor PU-H64''' | ||
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[[Category: Gewirth, D T.]] | [[Category: Gewirth, D T.]] | ||
[[Category: Immormino, R M.]] | [[Category: Immormino, R M.]] | ||
| - | [[Category: | + | [[Category: Chaperone]] |
| - | [[Category: | + | [[Category: Grp94]] |
| - | [[Category: | + | [[Category: H64]] |
| - | [[Category: | + | [[Category: H71]] |
| - | [[Category: | + | [[Category: Hsp90]] |
| - | [[Category: | + | [[Category: Pu3]] |
| - | [[Category: | + | [[Category: Purine]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 04:24:10 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 01:24, 4 May 2008
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. 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 Page seeded by OCA on Sun May 4 04:24:10 2008
Categories: Homo sapiens | Single protein | Gewirth, D T. | Immormino, R M. | Chaperone | Grp94 | H64 | H71 | Hsp90 | Pu3 | Purine
