title: Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex.
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.
authors.affiliation: Section of Structural Biology, Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Maruf M U
authors.initials: MM
authors.lastname: Ali
authors.forename: S Mark
authors.initials: SM
authors.lastname: Roe
authors.forename: Cara K
authors.initials: CK
authors.lastname: Vaughan
authors.forename: Phillipe
authors.initials: P
authors.lastname: Meyer
authors.forename: Barry
authors.initials: B
authors.lastname: Panaretou
authors.forename: Peter W
authors.initials: PW
authors.lastname: Piper
authors.forename: Chrisostomos
authors.initials: C
authors.lastname: Prodromou
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Pearl
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry* / Q000378:metabolism; D009711:Nucleotides / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D012441:Saccharomyces cerevisiae / Q000737:chemistry*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D009711:Nucleotides; C113025:SBA1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases