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Zierer, B.K.* ; Weiwad, M.* ; Rübbelke, M. ; Freiburger, L. ; Fischer, G.S.* ; Lorenz, O.R.* ; Sattler, M. ; Richter, K.H.* ; Buchner, J.*

Artificial accelerators of the molecular chaperone Hsp90 facilitate rate-limiting conformational transitions.

Angew. Chem.-Int. Edit. 53, 12257-12262 (2014)
Verlagsversion DOI
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
The molecular chaperone Hsp90 undergoes an ATP-driven cycle of conformational changes in which large structural rearrangements precede ATP hydrolysis. Wellestablished 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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Cancer ; Chaperones ; Cofactors ; Hsp90 Inhibition ; Protein Folding; Shock-protein 90; Atpase Activity; Cochaperone Aha1; Co-chaperones; Cycle; Binding; Cancer; Geldanamycin; Inhibition; Dissection
ISSN (print) / ISBN 1433-7851
e-ISSN 1521-3773
Quellenangaben Band: 53, Heft: 45, Seiten: 12257-12262 Artikelnummer: , Supplement: ,
Verlag Wiley
Verlagsort Weinheim
Begutachtungsstatus Peer reviewed