4NH8

Correlation between chemotype-dependent binding conformations of HSP90 alpha/beta and isoform selectivity

4NH8 の概要

• エントリーDOI: 10.2210/pdb4nh8/pdb
• 関連するPDBエントリー: 4NH7
• 分子名称: Heat shock protein HSP 90-alpha, 2-fluoro-6-[(3S)-tetrahydrofuran-3-ylamino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide (3 entities in total)
• 機能のキーワード: a/b protein, chaperone
• 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: 26582.86

構造登録者

Ernst, J.T.,Zuccola, H.J. (登録日: 2013-11-04, 公開日: 2014-01-15, 最終更新日: 2024-02-28)

主引用文献

Ernst, J.T.,Liu, M.,Zuccola, H.,Neubert, T.,Beaumont, K.,Turnbull, A.,Kallel, A.,Vought, B.,Stamos, D.
Correlation between chemotype-dependent binding conformations of HSP90 alpha / beta and isoform selectivity-Implications for the structure-based design of HSP90 alpha / beta selective inhibitors for treating neurodegenerative diseases.
Bioorg.Med.Chem.Lett., 24:204-208, 2014

PubMed Abstract: HSP90 continues to be a target of interest for neurodegeneration indications. Selective knockdown of the HSP90 cytosolic isoforms α and β is sufficient to reduce mutant huntingtin protein levels in vitro. Chemotype-dependent binding conformations of HSP90α/β appear to strongly influence isoform selectivity. The rational design of HSP90α/β inhibitors selective versus the mitochondrial (TRAP1) and endoplasmic reticulum (GRP94) isoforms offers a potential mitigating strategy for mechanism-based toxicities. Better tolerated HSP90 inhibitors would be attractive for targeting chronic neurodegenerative diseases such as Huntington's disease.

PubMed: 24332488
DOI: 10.1016/j.bmcl.2013.11.036

実験手法

X-RAY DIFFRACTION (1.65 Å)