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| [[Image:2fwz.jpg|left|200px]] | | {{Seed}} |
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| {{STRUCTURE_2fwz| PDB=2fwz | SCENE= }} | | {{STRUCTURE_2fwz| PDB=2fwz | SCENE= }} |
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| '''Structure of human Hsp90-alpha bound to the potent water soluble inhibitor PU-H71'''
| | ===Structure of human Hsp90-alpha bound to the potent water soluble inhibitor PU-H71=== |
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| ==Overview==
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| 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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_16884307}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 16884307 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_16884307}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Pu3]] | | [[Category: Pu3]] |
| [[Category: Purine]] | | [[Category: Purine]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 04:24:17 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 06:12:34 2008'' |
