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IridiumIII Luminescent Probe for Detection of the Malarial Protein Biomarker Histidine Rich Protein-II
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IridiumIII Luminescent Probe for Detection of the Malarial Protein Biomarker Histidine Rich Protein-II

Published on: July 7, 2015

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Imidazole-Imidazole Hydrogen Bonding in the pH-Sensing Histidine Side Chains of Influenza A M2

Kumar Tekwani Movellan1, Melanie Wegstroth1, Kerstin Overkamp1

  • 1Department of NMR Based Structural Biology , Max Planck Institute for Biophysical Chemistry , Am Fassberg 11 , Göttingen 37077 , Germany.

Journal of the American Chemical Society
|January 24, 2020
PubMed

Insights

Influenza A M2 channel histidine side chains form hydrogen bonds in their neutral state, influencing pH-dependent proton conduction essential for viral replication. This finding impacts understanding of M2 channel function and drug interactions.

Area of Science:

  • Structural biology
  • Virology
  • Biophysics

Background:

  • The influenza A M2 protein forms proton channels critical for viral uncoating.
  • Histidine side chain protonation states (pKa values) regulate M2 channel activity.
  • Previous models proposed water-associated or hydrogen-bonded histidine structures.

Purpose of the Study:

  • To investigate the structural arrangement of histidine side chains in the M2 channel conduction domain.
  • To determine the protonation state and interactions of histidine residues at physiological pH.
  • To elucidate the mechanism of pH-dependent proton conduction in the M2 channel.

Main Methods:

  • Utilized a conduction domain construct of the M2 protein reconstituted into lipid bilayers.
  • Employed solid-state Nuclear Magnetic Resonance (NMR) spectroscopy with 100 kHz magic-angle spinning.
  • Measured intermolecular 2hJNN coupling constants to probe hydrogen bonding interactions.

Main Results:

  • Observed that imidazole rings of histidine residues are hydrogen bonded even at pH 7.8 in the neutral charge state.
  • Detected an intermolecular 8.9 ± 0.3 Hz 2hJNN hydrogen bond between H37 Nε and Nδ.
  • This specific hydrogen bond interaction was absent in drug-bound M2 channel samples.

Conclusions:

  • Histidine residues in the M2 channel maintain a hydrogen-bonded quaternary structure at neutral pH.
  • This intrinsic hydrogen bonding influences the pKa values and pH-dependent proton conduction.
  • The observed interaction provides new insights into M2 channel gating and potential drug binding sites.

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