4Z1H

Crystal structure of human Trap1 with SMTIN-P01

4Z1H の概要

• エントリーDOI: 10.2210/pdb4z1h/pdb
• 関連するPDBエントリー: 4z1f 4z1g 4z1i
• 分子名称: Heat shock protein 75 kDa, mitochondrial, 8-[(6-iodo-1,3-benzodioxol-5-yl)sulfanyl]-9-[6-(triphenyl-lambda~5~-phosphanyl)hexyl]-9H-purin-6-amine (3 entities in total)
• 機能のキーワード: mitochondrial hsp90, chaperone
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Mitochondrion : Q12931
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 58181.73

構造登録者

Lee, C.,Park, H.K.,Ryu, J.H.,Kang, B.H. (登録日: 2015-03-27, 公開日: 2015-04-22, 最終更新日: 2024-10-23)

主引用文献

Lee, C.,Park, H.K.,Jeong, H.,Lim, J.,Lee, A.J.,Cheon, K.Y.,Kim, C.S.,Thomas, A.P.,Bae, B.,Kim, N.D.,Kim, S.H.,Suh, P.G.,Ryu, J.H.,Kang, B.H.
Development of a Mitochondria-Targeted Hsp90 Inhibitor Based on the Crystal Structures of Human TRAP1
J.Am.Chem.Soc., 137:4358-4367, 2015

PubMed Abstract: The mitochondrial pool of Hsp90 and its mitochondrial paralogue, TRAP1, suppresses cell death and reprograms energy metabolism in cancer cells; therefore, Hsp90 and TRAP1 have been suggested as target proteins for anticancer drug development. Here, we report that the actual target protein in cancer cell mitochondria is TRAP1, and current Hsp90 inhibitors cannot effectively inactivate TRAP1 because of their insufficient accumulation in the mitochondria. To develop mitochondrial TRAP1 inhibitors, we determined the crystal structures of human TRAP1 complexed with Hsp90 inhibitors. The isopropyl amine of the Hsp90 inhibitor PU-H71 was replaced with the mitochondria-targeting moiety triphenylphosphonium to produce SMTIN-P01. SMTIN-P01 showed a different mode of action from the nontargeted PU-H71, as well as much improved cytotoxicity to cancer cells. In addition, we determined the structure of a TRAP1-adenylyl-imidodiphosphate (AMP-PNP) complex. On the basis of comparative analysis of TRAP1 structures, we propose a molecular mechanism of ATP hydrolysis that is crucial for chaperone function.

PubMed: 25785725
DOI: 10.1021/ja511893n

実験手法

X-RAY DIFFRACTION (2.9 Å)