7c7b
Crystal structure of human TRAP1 with SJT009
Structural highlights
FunctionTRAP1_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 PubMedTumor necrosis factor receptor-associated protein 1 (TRAP1) is overexpressed in the mitochondria of various cancer cells, reprograms cellular metabolism to enable cancer cells to adapt to harsh tumor environments. As inactivation of TRAP1 induces massive apoptosis in cancer cells in vitro and in vivo, the development of TRAP1-selective inhibitors has become an attractive approach. A series of purine-8-one and pyrrolo[2,3-d]pyrimidine derivatives was developed based on TRAP1 structure and identified to be highly selective in vitro for TRAP1 over the paralogous enzymes, Hsp90alpha and Grp94. The TRAP1-selective inhibition strategy via utilization of the Asn171 residue of the ATP-lid was investigated using X-ray crystallography and molecular dynamics simulation studies. Among various synthesized potent TRAP1 inhibitors, 5f possessed a 65-fold selectivity over Hsp90alpha and a 13-fold selectivity over Grp94. Additionally, 6f had a half-maximal inhibitory concentration (IC50) of 63.5 nM for TRAP1, with a 78-fold and 30-fold selectivity over Hsp90alpha and Grp94, respectively. Design and Synthesis of TRAP1 Selective Inhibitors: H-Bonding with Asn171 Residue in TRAP1 Increases Paralog Selectivity.,Yang S, Yoon NG, Kim D, Park E, Kim SY, Lee JH, Lee C, Kang BH, Kang S ACS Med Chem Lett. 2021 Jun 16;12(7):1173-1180. doi:, 10.1021/acsmedchemlett.1c00213. eCollection 2021 Jul 8. PMID:34267888[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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