title: Artificial accelerators of the molecular chaperone Hsp90 facilitate rate-limiting conformational transitions.
abstract: The molecular chaperone Hsp90 undergoes an ATP-driven cycle of conformational changes in which large structural rearrangements precede ATP hydrolysis. Well-established small-molecule inhibitors of Hsp90 compete with ATP-binding. We wondered whether compounds exist that can accelerate the conformational cycle. In a FRET-based screen reporting on conformational rearrangements in Hsp90 we identified compounds. We elucidated their mode of action and showed that they can overcome the intrinsic inhibition in Hsp90 which prevents these rearrangements. The mode of action is similar to that of the co-chaperone Aha1 which accelerates the Hsp90 ATPase. However, while the two identified compounds influence conformational changes, they target different aspects of the structural transitions. Also, the binding site determined by NMR spectroscopy is distinct. This study demonstrates that small molecules are capable of triggering specific rate-limiting transitions in Hsp90 by mechanisms similar to those in protein cofactors.
authors.affiliation: Center for Integrated Protein Science Munich (CIPSM) Department Chemie, Technische Universität München, 85747 Garching (Germany).
authors.forename: Bettina K
authors.initials: BK
authors.lastname: Zierer
authors.forename: Matthias
authors.initials: M
authors.lastname: Weiwad
authors.forename: Martin
authors.initials: M
authors.lastname: Rübbelke
authors.forename: Lee
authors.initials: L
authors.lastname: Freiburger
authors.forename: Gunter
authors.initials: G
authors.lastname: Fischer
authors.forename: Oliver R
authors.initials: OR
authors.lastname: Lorenz
authors.forename: Michael
authors.initials: M
authors.lastname: Sattler
authors.forename: Klaus
authors.initials: K
authors.lastname: Richter
authors.forename: Johannes
authors.initials: J
authors.lastname: Buchner
mesh_terms: D031541:Fluorescence Resonance Energy Transfer; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry*; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation
chemical_list: D018841:HSP90 Heat-Shock Proteins
keywords: Hsp90 inhibition; cancer; chaperones; cofactors; protein folding