2H55

Structure of human Hsp90-alpha bound to the potent water soluble inhibitor PU-DZ8

2H55 の概要

• エントリーDOI: 10.2210/pdb2h55/pdb
• 関連するPDBエントリー: 1UY6 1ZW9 2FWY 2FWZ
• 分子名称: Heat shock protein HSP 90-alpha 4, 2-FLUORO-8-[(6-IODO-1,3-BENZODIOXOL-5-YL)METHYL]-9-[3-(ISOPROPYLAMINO)PROPYL]-9H-PURIN-6-AMINE (3 entities in total)
• 機能のキーワード: hsp90, grp94, chaperone, purine, pu3, h64, h71, dz8
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29285.47

構造登録者

Immormino, R.M.,Gewirth, D.T. (登録日: 2006-05-25, 公開日: 2006-10-03, 最終更新日: 2023-08-30)

主引用文献

Immormino, R.M.,Kang, Y.,Chiosis, G.,Gewirth, D.T.
Structural and quantum chemical studies of 8-aryl-sulfanyl adenine class Hsp90 inhibitors.
J.Med.Chem., 49:4953-4960, 2006

PubMed Abstract: 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.

PubMed: 16884307
DOI: 10.1021/jm060297x

実験手法

X-RAY DIFFRACTION (2 Å)