2WEQ

Yeast Hsp90 N-terminal domain LI-IV mutant with Geldanamycin

2WEQ の概要

• エントリーDOI: 10.2210/pdb2weq/pdb
• 関連するPDBエントリー: 1A4H 1AH6 1AH8 1AM1 1AMW 1BGQ 1HK7 1US7 1USU 1USV 1ZW9 1ZWH 2AKP 2BRC 2BRE 2CG9 2CGE 2CGF 2IWS 2IWU 2IWX 2VLS 2VW5 2VWC
• 分子名称: ATP-DEPENDENT MOLECULAR CHAPERONE HSP82, GELDANAMYCIN, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: atpase, cytoplasm, chaperone, atp-binding, phosphoprotein, stress response, nucleotide-binding
• 由来する生物種: SACCHAROMYCES CEREVISIAE (BAKER'S YEAST)
• 細胞内の位置: Cytoplasm: P02829
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 25604.20

構造登録者

Roe, S.M.,Prodromou, C.,Pearl, L.H. (登録日: 2009-04-01, 公開日: 2009-04-14, 最終更新日: 2024-05-01)

主引用文献

Prodromou, C.,Nuttall, J.M.,Millson, S.H.,Roe, S.M.,Sim, T.S.,Tan, D.,Workman, P.,Pearl, L.H.,Piper, P.W.
Structural Basis of the Radicicol Resistance Displayed by a Fungal Hsp90
Acs Chem.Biol., 4:289-, 2009

PubMed Abstract: Heat shock protein 90 (Hsp90) is a promising cancer drug target, as multiple oncogenic proteins are destabilized simultaneously when it loses its activity in tumor cells. Highly selective Hsp90 inhibitors, including the natural antibiotics geldanamycin (GdA) and radicicol (RAD), inactivate this essential molecular chaperone by occupying its nucleotide binding site. Often cancer drug therapy is compromised by the development of resistance, but a resistance to these Hsp90 inhibitors should not arise readily by mutation of those amino acids within Hsp90 that facilitate inhibitor binding, as these are required for the essential ATP binding/ATPase steps of the chaperone cycle and are tightly conserved. Despite this, the Hsp90 of a RAD-producing fungus is shown to possess an unusually low binding affinity for RAD but not GdA. Within its nucleotide binding site a normally conserved leucine is replaced by isoleucine, though the chaperone ATPase activity is not severely affected. Inserted into the Hsp90 of yeast, this conservative leucine to isoleucine substitution recreated this lowered affinity for RAD in vitro. It also generated a substantially enhanced resistance to RAD in vivo. Co-crystal structures reveal that the change to isoleucine is associated with a localized increase in the hydration of an Hsp90-bound RAD but not GdA. To the best of our knowledge, this is the first demonstration that it is possible for Hsp90 inhibitor resistance to arise by subtle alteration to the structure of Hsp90 itself.

PubMed: 19236053
DOI: 10.1021/CB9000316

実験手法

X-RAY DIFFRACTION (2.2 Å)