1OSF

Human Hsp90 in complex with 17-desmethoxy-17-N,N-Dimethylaminoethylamino-Geldanamycin

1OSF の概要

• エントリーDOI: 10.2210/pdb1osf/pdb
• 分子名称: heat shock 90kDa protein 1, alpha; heat shock 90kD protein 1, alpha, 17-DESMETHOXY-17-N,N-DIMETHYLAMINOETHYLAMINO-GELDANAMYCIN, (4S)-2-METHYL-2,4-PENTANEDIOL, ... (5 entities in total)
• 機能のキーワード: cell cycle
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P07900
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 25095.40

構造登録者

Jez, J.M.,Chen, J.C.-H.,Rastelli, G.,Stroud, R.M.,Santi, D.V. (登録日: 2003-03-19, 公開日: 2003-05-27, 最終更新日: 2024-02-14)

主引用文献

Jez, J.M.,Chen, J.C.,Rastelli, G.,Stroud, R.M.,Santi, D.V.
Crystal Structure and Molecular Modeling of 17-DMAG in Complex with Human Hsp90
Chem.Biol., 10:361-368, 2003

PubMed Abstract: Hsp90 is an attractive chemotherapeutic target because it chaperones the folding of proteins found in multiple signal transduction pathways. We describe the 1.75 A resolution crystal structure of human Hsp90 alpha (residues 9-236) complexed with 17-desmethoxy-17-N,N-dimethylaminoethylamino-geldanamycin (17-DMAG). The structure revealed an altered set of interactions between the 17-substituent and the protein compared to geldanamycin and the 17-dimethylaminoethyl moiety pointing into solvent, but otherwise was similar to that reported for the complex with geldanamycin. Targeted molecular dynamics simulations and energetic analysis indicate that geldanamycin undergoes two major conformational changes when it binds Hsp90, with the key step of the conversion being the trans to cis conformational change of the macrocycle amide bond. We speculate that 17-DMAG analogs constrained to a cis-amide in the ground state could provide a significant increase in affinity for Hsp90.

PubMed: 12725864
DOI: 10.1016/S1074-5521(03)00075-9

実験手法

X-RAY DIFFRACTION (1.75 Å)