5Y3O

Structure of TRAP1 complexed with DN320

5Y3O の概要

• エントリーDOI: 10.2210/pdb5y3o/pdb
• 分子名称: Heat shock protein 75 kDa, mitochondrial, 4-chloranyl-1-[(4-methoxy-3,5-dimethyl-pyridin-2-yl)methyl]pyrazolo[3,4-d]pyrimidin-6-amine (3 entities in total)
• 機能のキーワード: trap1, inhibitor, dn320, 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: 57740.85

構造登録者

Jeong, H.,Park, H.K.,Kang, S.,Kang, B.H.,Lee, C. (登録日: 2017-07-29, 公開日: 2017-08-30, 最終更新日: 2024-03-27)

主引用文献

Park, H.K.,Jeong, H.,Ko, E.,Lee, G.,Lee, J.E.,Lee, S.K.,Lee, A.J.,Im, J.Y.,Hu, S.,Kim, S.H.,Lee, J.H.,Lee, C.,Kang, S.,Kang, B.H.
Paralog Specificity Determines Subcellular Distribution, Action Mechanism, and Anticancer Activity of TRAP1 Inhibitors.
J. Med. Chem., 60:7569-7578, 2017

PubMed Abstract: Although Hsp90 inhibitors can inhibit multiple tumorigenic pathways in cancer cells, their anticancer activity has been disappointingly modest. However, by forcing Hsp90 inhibitors into the mitochondria with mitochondrial delivery vehicles, they were converted into potent drugs targeting the mitochondrial Hsp90 paralog TRAP1. Here, to improve mitochondrial drug accumulation without using the mitochondrial delivery vehicle, we increased freely available drug concentrations in the cytoplasm by reducing the binding of the drugs to the abundant cytoplasmic Hsp90. After analyzing X-ray cocrystal structures, the purine ring of the Hsp90 inhibitor 2 (BIIB021) was modified to pyrazolopyrimidine scaffolds. One pyrazolopyrimidine, 12b (DN401), bound better to TRAP1 than to Hsp90, inactivated the mitochondrial TRAP1 in vivo, and it exhibited potent anticancer activity. Therefore, the rationale and feasible guidelines for developing 12b can potentially be exploited to design a potent TRAP1 inhibitor.

PubMed: 28816449
DOI: 10.1021/acs.jmedchem.7b00978

実験手法

X-RAY DIFFRACTION (2.7 Å)