4Z1G
Crystal structure of human Trap1 with BIIB-021
Summary for 4Z1G
| Entry DOI | 10.2210/pdb4z1g/pdb |
| Related | 4z1f 4z1h 4z1i |
| Descriptor | Heat shock protein 75 kDa, mitochondrial, 6-chloro-9-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-9H-purin-2-amine (2 entities in total) |
| Functional Keywords | mitochondrial hsp90, chaperone |
| Biological source | Homo sapiens (Human) |
| Cellular location | Mitochondrion : Q12931 |
| Total number of polymer chains | 1 |
| Total formula weight | 57740.85 |
| Authors | Lee, C.,Park, H.K.,Ryu, J.H.,Kang, B.H. (deposition date: 2015-03-27, release date: 2015-04-22, Last modification date: 2024-11-20) |
| Primary citation | 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 Cited by 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: 25785725DOI: 10.1021/ja511893n PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.1 Å) |
Structure validation
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