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Structural and dynamic mechanisms for the function and inhibition of the M2 proton channel from influenza A virus.

ABSTRACT: The M2 proton channel from influenza A virus, a prototype for a class of viral ion channels known as viroporins, conducts protons along a chain of water molecules and ionizable sidechains, including His37. Recent studies highlight a delicate interplay between protein folding, proton binding, and proton conduction through the channel. Drugs inhibit proton conduction by binding to an aqueous cavity adjacent to M2's proton-selective filter, thereby blocking access of proton to the filter, and altering the energetic landscape of the channel and the energetics of proton-binding to His37.

SUBMITTER: Wang J

PROVIDER: S-EPMC3039100 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Structural and dynamic mechanisms for the function and inhibition of the M2 proton channel from influenza A virus.

Wang Jun J Qiu Jade Xiaoyan JX Soto Cinque C DeGrado William F WF

Current opinion in structural biology 20110117 1

The M2 proton channel from influenza A virus, a prototype for a class of viral ion channels known as viroporins, conducts protons along a chain of water molecules and ionizable sidechains, including His37. Recent studies highlight a delicate interplay between protein folding, proton binding, and proton conduction through the channel. Drugs inhibit proton conduction by binding to an aqueous cavity adjacent to M2's proton-selective filter, thereby blocking access of proton to the filter, and alter ...[more]

PMID: 21247754

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Structural basis for the function and inhibition of an influenza virus proton channel.

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Structure and mechanism of the M2 proton channel of influenza A virus.

Project description:The integral membrane protein M2 of influenza virus forms pH-gated proton channels in the viral lipid envelope. The low pH of an endosome activates the M2 channel before haemagglutinin-mediated fusion. Conductance of protons acidifies the viral interior and thereby facilitates dissociation of the matrix protein from the viral nucleoproteins--a required process for unpacking of the viral genome. In addition to its role in release of viral nucleoproteins, M2 in the trans-Golgi network (TGN) membrane prevents premature conformational rearrangement of newly synthesized haemagglutinin during transport to the cell surface by equilibrating the pH of the TGN with that of the host cell cytoplasm. Inhibiting the proton conductance of M2 using the anti-viral drug amantadine or rimantadine inhibits viral replication. Here we present the structure of the tetrameric M2 channel in complex with rimantadine, determined by NMR. In the closed state, four tightly packed transmembrane helices define a narrow channel, in which a 'tryptophan gate' is locked by intermolecular interactions with aspartic acid. A carboxy-terminal, amphipathic helix oriented nearly perpendicular to the transmembrane helix forms an inward-facing base. Lowering the pH destabilizes the transmembrane helical packing and unlocks the gate, admitting water to conduct protons, whereas the C-terminal base remains intact, preventing dissociation of the tetramer. Rimantadine binds at four equivalent sites near the gate on the lipid-facing side of the channel and stabilizes the closed conformation of the pore. Drug-resistance mutations are predicted to counter the effect of drug binding by either increasing the hydrophilicity of the pore or weakening helix-helix packing, thus facilitating channel opening.

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Project description: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 N?2 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-? 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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