Structural basis for proton conduction and inhibition by the influenza M2 protein

Mei Hong; William F. DeGrado

doi:10.1002/pro.2158

journal article Open Access Oct 09, 2012

Structural basis for proton conduction and inhibition by the influenza M2 protein

Mei Hong

William F. DeGrado

Protein Science Vol. 21 No. 11 pp. 1620-1633 · Wiley

View at Publisher Save 10.1002/pro.2158

Abstract

AbstractThe influenza M2 protein forms an acid‐activated and drug‐sensitive proton channel in the virus envelope that is important for the virus lifecycle. The functional properties and high‐resolution structures of this proton channel have been extensively studied to understand the mechanisms of proton conduction and drug inhibition. We review biochemical and electrophysiological studies of M2 and discuss how high‐resolution structures have transformed our understanding of this proton channel. Comparison of structures obtained in different membrane‐mimetic solvents and under different pH using X‐ray crystallography, solution NMR, and solid‐state NMR spectroscopy revealed how the M2 structure depends on the environment and showed that the pharmacologically relevant drug‐binding site lies in the transmembrane (TM) pore. Competing models of proton conduction have been evaluated using biochemical experiments, high‐resolution structural methods, and computational modeling. These results are converging to a model in which a histidine residue in the TM domain mediates proton relay with water, aided by microsecond conformational dynamics of the imidazole ring. These mechanistic insights are guiding the design of new inhibitors that target drug‐resistant M2 variants and may be relevant for other proton channels.

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Metrics

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Citations

112

References

Details

Published: Oct 09, 2012
Vol/Issue: 21(11)
Pages: 1620-1633
License: View

Authors

M

Mei Hong

Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

W

William F. DeGrado

University of California, San Francisco

Funding

NIH Award: GM088204 (M.H.); GM56423, GM54616, and AI74571 (W.F.D.)

NSF Award: MCB0543473 (M.H.)

Cite This Article

Mei Hong, William F. DeGrado (2012). Structural basis for proton conduction and inhibition by the influenza M2 protein. Protein Science, 21(11), 1620-1633. https://doi.org/10.1002/pro.2158

Structural basis for proton conduction and inhibition by the influenza M2 protein

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