5Y3O
Structure of TRAP1 complexed with DN320
Summary for 5Y3O
| Entry DOI | 10.2210/pdb5y3o/pdb |
| Descriptor | 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) |
| Functional Keywords | trap1, inhibitor, dn320, mitochondrial hsp90, chaperone |
| Biological source | Homo sapiens (Human) |
| Cellular location | Mitochondrion : Q12931 |
| Total number of polymer chains | 1 |
| Total formula weight | 57740.85 |
| Authors | Jeong, H.,Park, H.K.,Kang, S.,Kang, B.H.,Lee, C. (deposition date: 2017-07-29, release date: 2017-08-30, Last modification date: 2024-03-27) |
| Primary citation | 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 Cited by 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: 28816449DOI: 10.1021/acs.jmedchem.7b00978 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.7 Å) |
Structure validation
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