title: Development of a mitochondria-targeted Hsp90 inhibitor based on the crystal structures of human TRAP1.
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.
authors.forename: Changwook
authors.initials: C
authors.lastname: Lee
authors.forename: Hye-Kyung
authors.initials: HK
authors.lastname: Park
authors.forename: Hanbin
authors.initials: H
authors.lastname: Jeong
authors.forename: Jaehwa
authors.initials: J
authors.lastname: Lim
authors.forename: An-Jung
authors.initials: AJ
authors.lastname: Lee
authors.forename: Keun Young
authors.initials: KY
authors.lastname: Cheon
authors.forename: Chul-Su
authors.initials: CS
authors.lastname: Kim
authors.forename: Ajesh P
authors.initials: AP
authors.lastname: Thomas
authors.forename: Boram
authors.initials: B
authors.lastname: Bae
authors.affiliation: ∥New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 701-310, Korea.
authors.forename: Nam Doo
authors.initials: ND
authors.lastname: Kim
authors.affiliation: ∥New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 701-310, Korea.
authors.forename: Seong Heon
authors.initials: SH
authors.lastname: Kim
authors.forename: Pann-Ghill
authors.initials: PG
authors.lastname: Suh
authors.forename: Ja-Hyoung
authors.initials: JH
authors.lastname: Ryu
authors.forename: Byoung Heon
authors.initials: BH
authors.lastname: Kang
mesh_terms: D000588:Amines / Q000737:chemistry; D052117:Benzodioxoles / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D008958:Models, Molecular; D009943:Organophosphorus Compounds / Q000737:chemistry; D055503:Protein Multimerization; D055550:Protein Stability; D020836:Protein Structure, Quaternary; D011687:Purines / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000588:Amines; D052117:Benzodioxoles; D018841:HSP90 Heat-Shock Proteins; D009943:Organophosphorus Compounds; D011687:Purines; C092306:TRAP1 protein, human; C526550:9H-purine-9-propanamine, 6-amino-8-((6-iodo-1,3-benzodioxol-5-yl)thio)-N-(1-methylethyl)-