5y3n | pdb_00005y3n
Structure of TRAP1 complexed with DN401
Structural highlights
Function[TRAP1_HUMAN] Chaperone that expresses an ATPase activity. Involved in maintaining mitochondrial function and polarization, most likely through stabilization of mitochondrial complex I. Is a negative regulator of mitochondrial respiration able to modulate the balance between oxidative phosphorylation and aerobic glycolysis. The impact of TRAP1 on mitochondrial respiration is probably mediated by modulation of mitochondrial SRC and inhibition of SDHA.[1] [2] [3] Publication Abstract from PubMedAlthough 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 BIIB021 was modified to pyrazolopyrimidine scaffolds. One pyrazolopyrimidine, 3b (DN401), bound better to TRAP1 than to Hsp90, inactivated the mitochondrial TRAP1 in vivo, and exhibited potent anticancer activity. Therefore, the rationale and feasible guidelines for developing 3b can potentially be exploited to design a potent TRAP1 inhibitor. Paralog specificity determines subcellular distribution, action mechanism, and anticancer activity of TRAP1 inhibitors.,Park HK, Jeong H, Ko E, Lee G, Lee JE, Lee SK, Lee AJ, Im JY, Hu S, Kim SH, Lee JH, Lee C, Kang S, Kang BH J Med Chem. 2017 Aug 17. doi: 10.1021/acs.jmedchem.7b00978. PMID:28816449[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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