Structural and computational biology of the molecular chaperone Hsp90: from understanding molecular mechanisms to computer-based inhibitor design.
The molecular chaperone Hsp90 (90 kDa heat-shock protein) mediates many fundamental cellular pathways involved in cell proliferation, cell survival, and cellular stress response. Hsp90 is responsible for the correct conformational development, stability and function in crowded cell environments. Structural and computational biology studies have recently provided important insights into underlying molecular mechanisms of Hsp90 function. These developments have revealed a critical role of Hsp90 structure, conformational dynamics and interdomain communication in promoting the binding and release of ligands and its interaction with client proteins. By disabling multiple signal transduction pathways, Hsp90 inhibition provides a powerful therapeutic strategy in cancer research, which is selective for specific cancer mechanisms, yet broadly applicable to disparate tumors with different genetic signatures. Herein, we review the recent developments in structural and computational studies of Hsp90 function and binding, with the emphasis on progress towards computational structure-based discovery and design of Hsp90 inhibitors. We also review the emerging insights from computational and structure-based approaches to develop anticancer therapies that can target novel allosteric binding sites and Hsp90 interactions with co-chaperones and client proteins. Structural and computational biology studies can provide a foundation for the design of Hsp90 modulators capable of regulating functional protein motions linked to biological activities. We highlight current challenges in translating molecular mechanisms of the molecular chaperone into therapeutic strategies and outline future directions for the computer-based design of Hsp90 inhibitors.
Department of Pharmaceutical Chemistry, School of Pharmacy, The University of Kansas, Lawrence, KS 66047, USA. verk@ku.edu
Gennady M
GM
Verkhivker
Anshuman
A
Dixit
Giulia
G
Morra
Giorgio
G
Colombo
D000818:Animals; D019295:Computational Biology; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D011487:Protein Conformation / Q000187:drug effects; D013329:Structure-Activity Relationship
D018841:HSP90 Heat-Shock Proteins