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Dynorphin Neuropeptides Decrease Apparent Proton Affinity of ASIC1a by Occluding the Acidic Pocket

  • Lilia Leisle*
    Lilia Leisle
    Institute of Physiology, RWTH Aachen University, 52074 Aachen, Germany
    *Email: [email protected]
    More by Lilia Leisle
  • Michael Margreiter
    Michael Margreiter
    Computational Biomedicine−Institute for Advanced Simulation/Institute of Neuroscience and Medicine, Forschungszentrum Jülich, 52425 Jülich, Germany
    Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
  • Audrey Ortega-Ramírez
    Audrey Ortega-Ramírez
    Institute of Physiology, RWTH Aachen University, 52074 Aachen, Germany
  • Elinor Cleuvers
    Elinor Cleuvers
    Institute of Physiology, RWTH Aachen University, 52074 Aachen, Germany
  • Michèle Bachmann
    Michèle Bachmann
    Institute of Physiology, RWTH Aachen University, 52074 Aachen, Germany
  • Giulia Rossetti
    Giulia Rossetti
    Computational Biomedicine−Institute for Advanced Simulation/Institute of Neuroscience and Medicine, Forschungszentrum Jülich, 52425 Jülich, Germany
    Jülich Supercomputing Center (JSC), Forschungszentrum Jülich, 52425 Jülich, Germany
    Department of Neurology, RWTH Aachen University, 52074 Aachen, Germany
  • , and 
  • Stefan Gründer*
    Stefan Gründer
    Institute of Physiology, RWTH Aachen University, 52074 Aachen, Germany
    *Email: [email protected]
Cite this: J. Med. Chem. 2021, 64, 18, 13299–13311
Publication Date (Web):August 30, 2021
https://doi.org/10.1021/acs.jmedchem.1c00447
Copyright © 2021 The Authors. Published by American Chemical Society
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Supporting Info (3)»

Abstract

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Prolonged acidosis, as it occurs during ischemic stroke, induces neuronal death via acid-sensing ion channel 1a (ASIC1a). Concomitantly, it desensitizes ASIC1a, highlighting the pathophysiological significance of modulators of ASIC1a acid sensitivity. One such modulator is the opioid neuropeptide big dynorphin (Big Dyn) which binds to ASIC1a and enhances its activity during prolonged acidosis. The molecular determinants and dynamics of this interaction remain unclear, however. Here, we present a molecular interaction model showing a dynorphin peptide inserting deep into the acidic pocket of ASIC1a. We confirmed experimentally that the interaction is predominantly driven by electrostatic forces, and using noncanonical amino acids as photo-cross-linkers, we identified 16 residues in ASIC1a contributing to Big Dyn binding. Covalently tethering Big Dyn to its ASIC1a binding site dramatically decreased the proton sensitivity of channel activation, suggesting that Big Dyn stabilizes a resting conformation of ASIC1a and dissociates from its binding site during channel opening.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c00447.

  • (1) Nine supporting figures, illustrating details of MD simulation, additional western blots, functional analysis and representative current traces of ASIC1a mutants, and purity of Big Dyn (PDF)

  • (2) Homology model (PDB)

  • (3) Video of the last 40 ns of the MD simulation of the ASIC1a-Dyn A(1-13) interaction during complex (MP4)

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Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

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