ArticleJournal of the American Chemical Society2012
Paramagnetic Cu(II) for probing membrane protein structure and function: inhibition mechanism of the influenza M2 proton channel.
Article in Journal of the American Chemical Society, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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21 citing papers in PubMed, 44 citations in OpenAlex.
- Caught in the Middle: A Rigid DNA Label That Provides an Incisive Picture of DNA Conformational Flexibility in Protein-DNA Complexes.Journal of the American Chemical Society · 2025Article
- Rapid Determination of the Topology of Oligomeric α-Helical Membrane Proteins by Water- and Lipid-Edited Methyl NMR.The journal of physical chemistry. B · 2023Article
- Non-Negligible Role of Trace Elements in Influenza Virus Infection.Metabolites · 2023Review
- Mechanism and Kinetics of Copper Complexes Binding to the Influenza A M2 S31N and S31N/G34E Channels.Biophysical journal · 2021Article
- Solid-state NMR spectroscopy.Nature reviews. Methods primers · 2021Article
- Fluorinated ZnFeACS omega · 2020Article
- Viroporins in the Influenza Virus.Cells · 2019Review
- Structural Studies of Amyloid Fibrils by Paramagnetic Solid-State Nuclear Magnetic Resonance Spectroscopy.Journal of the American Chemical Society · 2018Article
- Fast Magic-Angle-SpinningThe journal of physical chemistry. B · 2018Article
- Functional studies reveal the similarities and differences between AM2 and BM2 proton channels from influenza viruses.Biochimica et biophysica acta. Biomembranes · 2018Article
- The Target of β-Expansin EXPB1 in Maize Cell Walls from Binding and Solid-State NMR Studies.Plant physiology · 2016Article
- Functional and Biochemical Characterization of Cucumber Genes Encoding Two Copper ATPases CsHMA5.1 and CsHMA5.2.The Journal of biological chemistry · 2015Article
- Paramagnetic relaxation enhancement of membrane proteins by incorporation of the metal-chelating unnatural amino acid 2-amino-3-(8-hydroxyquinolin-3-yl)propanoic acid (HQA).Journal of biomolecular NMR · 2015Article
- Cardiolipin interaction with subunit c of ATP synthase: solid-state NMR characterization.Biochimica et biophysica acta · 2015Article
- Probing membrane protein structure using water polarization transfer solid-state NMR.Journal of magnetic resonance (San Diego, Calif. : 1997) · 2014Article
- Capturing a reactive state of amyloid aggregates: NMR-based characterization of copper-bound Alzheimer disease amyloid β-fibrils in a redox cycle.The Journal of biological chemistry · 2014Article
- Paramagnetic doping of a 7TM membrane protein in lipid bilayers by Gd³⁺-complexes for solid-state NMR spectroscopy.Journal of biomolecular NMR · 2014Article
- Article
- Structural basis for proton conduction and inhibition by the influenza M2 protein.Protein science : a publication of the Protein Society · 2012Review
- Hydrogen-bonding partner of the proton-conducting histidine in the influenza M2 proton channel revealed from 1H chemical shifts.Journal of the American Chemical Society · 2012Article
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3 authors at 1 institution in 1 country.
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Abstract
Paramagnetic Cu(II) ions enhance nuclear spin relaxation in a distance-dependent fashion and can be used as a structural probe of proteins. Cu(II) can also serve as a functionally important ligand in proteins. Here we investigate the structural basis of Cu(II) inhibition of the influenza M2 proton channel through Cu(II)-induced paramagnetic relaxation enhancement (PRE). (13)C T(1) relaxation rates of the central residues of the transmembrane (TM) domain of M2 are significantly enhanced by Cu(II), and pronounced spectral broadening is observed for the proton-selective residue, His37. These data yielded quantitative distances of (13)C spins to the Cu(II) center and identified the Cu(II) binding site to be Nε2 of His37. This binding site is surrounded by four imidazole rings from the top and four indole rings of Trp41 from the bottom, thus explaining the high affinity of Cu(II) binding. Bound at this location, Cu(II) can inhibit proton currents by perturbing histidine-water proton exchange, preventing histidine conformational dynamics, and interfering with His-Trp cation-π interaction. The Cu(II) binding site is distinct from the binding site of the hydrophobic drug amantadine, which is about 10 Å N-terminal to His37. Consistently, Cu(II) and amantadine induce distinct conformational changes at several key residues, suggesting the possibility of designing new drugs that target the His37 site to inhibit amantadine-resistant mutant M2 proteins. In addition to the high-affinity His37 binding site, we also examined the weaker and nonspecific binding of Cu(II) to membrane-surface lipid phosphates and the extent of the resulting PRE to surface-proximal protein residues. This study demonstrates the feasibility of NMR studies of paramagnetic-ion-complexed membrane proteins, where the ion serves as both a functional ligand and a distance probe.
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