7C7C

Crystal structure of human TRAP1 with SJT104

7C7C の概要

• エントリーDOI: 10.2210/pdb7c7c/pdb
• 分子名称: Heat shock protein 75 kDa, mitochondrial, 2-azanyl-9-[(4-bromanyl-2-fluoranyl-phenyl)methyl]-6-chloranyl-purin-8-ol (2 entities in total)
• 機能のキーワード: trpa1, selectivity, mitochondria, hsp90, anticancer, drug, 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: 57794.67

構造登録者

Kim, D.,Yang, S.,Yoon, N.G.,Park, E.,Kim, S.Y.,Kang, B.H.,Lee, C.,Kang, S. (登録日: 2020-05-24, 公開日: 2021-05-26, 最終更新日: 2023-11-29)

主引用文献

Yang, S.,Yoon, N.G.,Kim, D.,Park, E.,Kim, S.Y.,Lee, J.H.,Lee, C.,Kang, B.H.,Kang, S.
Design and Synthesis of TRAP1 Selective Inhibitors: H-Bonding with Asn171 Residue in TRAP1 Increases Paralog Selectivity.
Acs Med.Chem.Lett., 12:1173-1180, 2021

PubMed Abstract: Tumor necrosis factor receptor-associated protein 1 (TRAP1) is overexpressed in the mitochondria of various cancer cells, reprograms cellular metabolism to enable cancer cells to adapt to harsh tumor environments. As inactivation of TRAP1 induces massive apoptosis in cancer cells and , the development of TRAP1-selective inhibitors has become an attractive approach. A series of purine-8-one and pyrrolo[2,3-]pyrimidine derivatives was developed based on TRAP1 structure and identified to be highly selective in vitro for TRAP1 over the paralogous enzymes, Hsp90α and Grp94. The TRAP1-selective inhibition strategy via utilization of the Asn171 residue of the ATP-lid was investigated using X-ray crystallography and molecular dynamics simulation studies. Among various synthesized potent TRAP1 inhibitors, possessed a 65-fold selectivity over Hsp90α and a 13-fold selectivity over Grp94. Additionally, had a half-maximal inhibitory concentration (IC) of 63.5 nM for TRAP1, with a 78-fold and 30-fold selectivity over Hsp90α and Grp94, respectively.

PubMed: 34267888
DOI: 10.1021/acsmedchemlett.1c00213

実験手法

X-RAY DIFFRACTION (3 Å)