Crystal structure of an Hsp90–nucleotide–p23/Sba1 closed chaperone complex

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. The molecular chaperone Hsp90 activates many oncogenic proteins whose mutation or disregulation drives cancer. It depends on ATP, and inhibition of ATP binding blocks oncogene activation. All this makes Hsp90 a prime target for rational chemotherapy. Its biochemistry is poorly understood, though, and the means by which it utilizes ATP is contentious. Ali et al. have now determined the structure of Hsp90 in a complex with ATP and a co-chaperone. It reveals how the ATP-coupled chaperone cycle works, and how it drives conformational change in 'client' proteins dependent on Hsp90. The structure of full-length Hsp90 in association with an ATP analogue and a co-chaperone details for the first time how ATP binding changes Hsp90's conformation, and how the co-chaperone stabilizes the overall structure so that target proteins can bind.