Artificial Accelerators of the Molecular Chaperone Hsp90 Facilitate Rate‐Limiting Conformational Transitions1. Issue 45 (22nd September 2014)

• Record Type: Journal Article
• Authors: Zierer, Bettina K.; Weiwad, Matthias; Rübbelke, Martin; Freiburger, Lee; Fischer, Gunter; Lorenz, Oliver R.; Sattler, Michael; Richter, Klaus; Buchner, Johannes
• Is Part Of: Angewandte Chemie international edition. Volume 53:Issue 45(2014)
• Page Start: 12257
• Page End: 12262
• Publication Date: 2014-09-22
• Subjects: Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201406578
• Languages: English
• ISSNs: 1433-7851

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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.</p> </abstract>