Heat shock protein 90 (Hsp90) is an ubiquitous molecular chaperone responsible for the assembly and regulation of many signal transduction and regulatory client proteins. Since Hsp90 refolds, stabilizes and regulates the trafficking of many proteins responsible for uncontrolled proliferation and apoptotic resistance, including multiple protein kinases, steroid hormone receptors, mutated p53, survivin and others, this chaperone is an emerging target for the development of anticancer drugs.1,2 Hsp90 is a large and conformationally dynamic protein that undergoes dramatic conformational changes upon ATP binding and hydrolysis. Crystallography, small-angle X-ray scattering and electron microscopy techniques have revealed an underlying conformational complexity of Hsp90, which is composed by three highly dynamic domains, the N-terminal (NTD), middle (MD) and C-terminal (CTD) domains.3 Dimerization is an essential step of the Hsp90 cycle. Recently, the crystal structure of yeast Hsp90 in complex with an ATP analogue and the co-chaperone p23/Sba1 revealed the architecture of the closed and compact homodimer, providing a view of Hsp90 in the ATP-bound state, which represents an obliged conformation along the ATPase cycle.4 This work reports the results of a molecular dynamics and dimerization free energy analysis performed on the structure of a human Hsp90 homology model in the closed conformation. Decomposition of free energies on a residue basis led to the prediction of five clusters of dimerization hot spots, three of which are located in the NTD while the other two in the CTD. These residues represent valuable candidates for future mutagenesis studies and may provide new sites for the design of allosteric inhibitors.
|Data di pubblicazione:||2014|
|Titolo:||Dimerization hot spots in the structure of human Hsp90|
|Digital Object Identifier (DOI):||10.1039/c4md00094c|
|Appare nelle tipologie:||Articolo su rivista|
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