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Visualizing the transiently populated closed-state of human HSP90 ATP binding domain

Author

Listed:
  • Faustine Henot

    (Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale (IBS))

  • Elisa Rioual

    (Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale (IBS)
    University of Lyon, Université Claude Bernard Lyon 1)

  • Adrien Favier

    (Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale (IBS))

  • Pavel Macek

    (Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale (IBS)
    NMR-Bio)

  • Elodie Crublet

    (NMR-Bio)

  • Pierre Josso

    (University of Lyon, Université Claude Bernard Lyon 1)

  • Bernhard Brutscher

    (Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale (IBS))

  • Matthias Frech

    (Discovery Technologies, Merck KGaA)

  • Pierre Gans

    (Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale (IBS))

  • Claire Loison

    (University of Lyon, Université Claude Bernard Lyon 1)

  • Jerome Boisbouvier

    (Univ. Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale (IBS))

Abstract

HSP90 are abundant molecular chaperones, assisting the folding of several hundred client proteins, including substrates involved in tumor growth or neurodegenerative diseases. A complex set of large ATP-driven structural changes occurs during HSP90 functional cycle. However, the existence of such structural rearrangements in apo HSP90 has remained unclear. Here, we identify a metastable excited state in the isolated human HSP90α ATP binding domain. We use solution NMR and mutagenesis to characterize structures of both ground and excited states. We demonstrate that in solution the HSP90α ATP binding domain transiently samples a functionally relevant ATP-lid closed state, distant by more than 30 Å from the ground state. NMR relaxation enables to derive information on the kinetics and thermodynamics of this interconversion, while molecular dynamics simulations establish that the ATP-lid in closed conformation is a metastable exited state. The precise description of the dynamics and structures sampled by human HSP90α ATP binding domain provides information for the future design of new therapeutic ligands.

Suggested Citation

  • Faustine Henot & Elisa Rioual & Adrien Favier & Pavel Macek & Elodie Crublet & Pierre Josso & Bernhard Brutscher & Matthias Frech & Pierre Gans & Claire Loison & Jerome Boisbouvier, 2022. "Visualizing the transiently populated closed-state of human HSP90 ATP binding domain," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35399-8
    DOI: 10.1038/s41467-022-35399-8
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    References listed on IDEAS

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    1. Sophie L. Mader & Abraham Lopez & Jannis Lawatscheck & Qi Luo & Daniel A. Rutz & Ana P. Gamiz-Hernandez & Michael Sattler & Johannes Buchner & Ville R. I. Kaila, 2020. "Conformational dynamics modulate the catalytic activity of the molecular chaperone Hsp90," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    2. Jonathan Schubert & Andrea Schulze & Chrisostomos Prodromou & Hannes Neuweiler, 2021. "Two-colour single-molecule photoinduced electron transfer fluorescence imaging microscopy of chaperone dynamics," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    3. Vincenzo Venditti & Vitali Tugarinov & Charles D. Schwieters & Alexander Grishaev & G. Marius Clore, 2015. "Large interdomain rearrangement triggered by suppression of micro- to millisecond dynamics in bacterial Enzyme I," Nature Communications, Nature, vol. 6(1), pages 1-9, May.
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