7U8V

hTRAP1 with inhibitors

7U8V の概要

• エントリーDOI: 10.2210/pdb7u8v/pdb
• 分子名称: Heat shock protein 75 kDa, mitochondrial, (4-hydroxy-1,3-phenylene)bis[(2H-isoindol-2-yl)methanone] (3 entities in total)
• 機能のキーワード: htrap1, inhibitor, chaperone
• 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: 55961.56

構造登録者

Deng, J.,Matts, R.,Peng, S. (登録日: 2022-03-09, 公開日: 2023-08-16, 最終更新日: 2026-03-04)

主引用文献

Merfeld, T.,Peng, S.,Keegan, B.M.,Crowley, V.M.,Brackett, C.M.,Gutierrez, A.,McCann, N.R.,Reynolds, T.S.,Rhodes, M.C.,Byrd, K.M.,Deng, J.,Matts, R.L.,Blagg, B.S.J.
Elucidation of novel TRAP1-Selective inhibitors that regulate mitochondrial processes.
Eur.J.Med.Chem., 258:115531-115531, 2023

PubMed Abstract: Hsp90 isoform-selective inhibitors represent a new paradigm for novel anti-cancer drugs as each of the four isoforms have specific cellular localization, function, and client proteins. The mitochondrial isoform, TRAP1, is the least understood member of the Hsp90 family due to the lack of small molecule tools to study its biological function. Herein, we report novel TRAP1-selective inhibitors used to interrogate TRAP1's biological function along with co-crystal structures of such compounds bound to the N-terminus of TRAP1. Solution of the co-crystal structure allowed for a structure-based approach that resulted in compound 36, which is a 40 nM inhibitor with >250-fold TRAP1 selectivity over Grp94, the isoform with the highest structural similarity to TRAP1 within the N-terminal ATP binding site. Lead compounds 35 and 36 were found to selectively induce TRAP1 client protein degradation without inducing the heat shock response or disrupting Hsp90-cytosolic clients. They were also shown to inhibit OXPHOS, alter cellular metabolism towards glycolysis, disrupt TRAP1 tetramer stability, and disrupt the mitochondrial membrane potential.

PubMed: 37307624
DOI: 10.1016/j.ejmech.2023.115531

実験手法

X-RAY DIFFRACTION (1.448 Å)