1. Section of Structural Biology, Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK
2. Pharmaceutical Science Research Division, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NN, UK
3. Department of Molecular Biology and Biotechnology, The University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, UK
4. †Present address: Laboratoire d'Enzymologie et de Biochimie Structurales, CNRS, Avenue de la Terrasse, 91198 Gif sur Yvette, France

Correspondence to: Laurence H. Pearl¹ Correspondence and requests for materials should be addressed to L.H.P. (Email: laurence.pearl@icr.ac.uk). Coordinates and structure factors for the Hsp90–p23/Sba1–AMP-PNP complex and M-C construct have been deposited in the Protein Data Bank with accession codes 2CGE and 2CG9.

Abstract

Hsp90 (heat shock protein of 90 kDa) is a ubiquitous molecular chaperone responsible for the assembly and regulation of many eukaryotic signalling systems and is an emerging target for rational chemotherapy of many cancers. Although the structures of isolated domains of Hsp90 have been determined, the arrangement and ATP-dependent dynamics of these in the full Hsp90 dimer have been elusive and contentious. Here we present the crystal structure of full-length yeast Hsp90 in complex with an ATP analogue and the co-chaperone p23/Sba1. The structure reveals the complex architecture of the 'closed' state of the Hsp90 chaperone, the extensive interactions between domains and between protein chains, the detailed conformational changes in the amino-terminal domain that accompany ATP binding, and the structural basis for stabilization of the closed state by p23/Sba1. Contrary to expectations, the closed Hsp90 would not enclose its client proteins but provides a bipartite binding surface whose formation and disruption are coupled to the chaperone ATPase cycle.

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