Artificial Accelerators of the Molecular Chaperone Hsp90 Facilitate Rate‐Limiting Conformational Transitions |
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Authors: | Bettina K Zierer Matthias Weiwad Martin Rübbelke Lee Freiburger Gunter Fischer Oliver R Lorenz Michael Sattler Klaus Richter Johannes Buchner |
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Institution: | 1. Center for Integrated Protein Science Munich (CIPSM) Department Chemie, Technische Universit?t München, 85747 Garching (Germany);2. Max Planck Research Unit for Enzymology of Protein Folding, Weinbergweg 22, 06120 Halle/Saale (Germany);3. Present address: Martin‐Luther Universit?t Halle Wittenberg, Institute of Biochemistry (Germany);4. Institute of Structural Biology, Helmholtz Zentrum München, 85764 Neuherberg (Germany);5. Present address: Max‐Planck‐Institute of Biophysical Chemistry G?ttingen (Germany) |
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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. |
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Keywords: | cancer chaperones cofactors Hsp90 inhibition protein folding |
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