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Free energy landscape of activation in a signalling protein at atomic resolution

Author

Listed:
  • F. Pontiggia

    (Brandeis University)

  • D.V. Pachov

    (Brandeis University)

  • M.W. Clarkson

    (Brandeis University)

  • J. Villali

    (Brandeis University)

  • M.F. Hagan

    (Brandeis University)

  • V.S. Pande

    (NIH Center for Biomedical Computation, Stanford University)

  • D. Kern

    (Brandeis University)

Abstract

The interconversion between inactive and active protein states, traditionally described by two static structures, is at the heart of signalling. However, how folded states interconvert is largely unknown due to the inability to experimentally observe transition pathways. Here we explore the free energy landscape of the bacterial response regulator NtrC by combining computation and nuclear magnetic resonance, and discover unexpected features underlying efficient signalling. We find that functional states are defined purely in kinetic and not structural terms. The need of a well-defined conformer, crucial to the active state, is absent in the inactive state, which comprises a heterogeneous collection of conformers. The transition between active and inactive states occurs through multiple pathways, facilitated by a number of nonnative transient hydrogen bonds, thus lowering the transition barrier through both entropic and enthalpic contributions. These findings may represent general features for functional conformational transitions within the folded state.

Suggested Citation

  • F. Pontiggia & D.V. Pachov & M.W. Clarkson & J. Villali & M.F. Hagan & V.S. Pande & D. Kern, 2015. "Free energy landscape of activation in a signalling protein at atomic resolution," Nature Communications, Nature, vol. 6(1), pages 1-14, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8284
    DOI: 10.1038/ncomms8284
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    Cited by:

    1. Fabian Bumbak & James B. Bower & Skylar C. Zemmer & Asuka Inoue & Miquel Pons & Juan Carlos Paniagua & Fei Yan & James Ford & Hongwei Wu & Scott A. Robson & Ross A. D. Bathgate & Daniel J. Scott & Pau, 2023. "Stabilization of pre-existing neurotensin receptor conformational states by β-arrestin-1 and the biased allosteric modulator ML314," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Mitchell Brüderlin & Raphael Böhm & Firas Fadel & Sebastian Hiller & Tilman Schirmer & Badri N. Dubey, 2023. "Structural features discriminating hybrid histidine kinase Rec domains from response regulator homologs," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Trayder Thomas & Benoît Roux, 2021. "Tyrosine kinases: complex molecular systems challenging computational methodologies," The European Physical Journal B: Condensed Matter and Complex Systems, Springer;EDP Sciences, vol. 94(10), pages 1-13, October.

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