Open AccessMutations Y493G and K546D in human HSP 90 disrupt binding of celastrol and reduce interaction with Cdc37
Author(s) -
Peng Bin,
Gu YiJun,
Wang Ying,
Cao FanFan,
Zhang Xue,
Zhang DengHai,
Hou Jian
Publication year - 2016
Publication title -
febs open bio
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.718
H-Index - 31
ISSN - 2211-5463
DOI - 10.1002/2211-5463.12081
Subject(s) - celastrol , heat shock protein , chemistry , isothermal titration calorimetry , biochemistry , hsp90 , dimer , docking (animal) , plasma protein binding , biophysics , biology , medicine , gene , apoptosis , nursing , organic chemistry
Celastrol, a natural compound derived from the Chinese herb Tripterygium wilfordii Hook F, has been proven to inhibit heat shock protein 90 ( HSP 90) activity and has attracted much attention because of its promising effects in cancer treatment and in ameliorating degenerative neuron diseases. However, the HSP 90 structure involved in celastrol interaction is not known. Here, we report a novel celastrol‐binding pocket in the HSP 90 dimer, predicted by molecular docking. Mutation of the two key binding pocket amino acids (Lys546 and Tyr493) disrupted the binding of celastrol to HSP 90 dimers, as detected by isothermal titration calorimetry ( ITC ). Interestingly, such mutations also reduced binding between HSP 90 and the cochaperone Cdc37, thus providing a new explanation for reported findings that celastrol shows more obvious effects in disrupting binding between HSP 90 and Cdc37 than between HSP 90 and other cochaperones. In short, our work discloses a novel binding pocket in HSP 90 dimer for celastrol and provides an explanation as to why celastrol has a strong effect on HSP 90 and Cdc37 binding.