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PDBsum entry 4z1h
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References listed in PDB file
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Key reference
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Title
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Development of a mitochondria-Targeted hsp90 inhibitor based on the crystal structures of human trap1.
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Authors
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C.Lee,
H.K.Park,
H.Jeong,
J.Lim,
A.J.Lee,
K.Y.Cheon,
C.S.Kim,
A.P.Thomas,
B.Bae,
N.D.Kim,
S.H.Kim,
P.G.Suh,
J.H.Ryu,
B.H.Kang.
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Ref.
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J Am Chem Soc, 2015,
137,
4358-4367.
[DOI no: ]
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PubMed id
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Abstract
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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.
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