Structure of the amantadine binding site of influenza M2 proton channels in lipid bilayers

Simple item page
dc.contributor.author Cady, Sarah
dc.contributor.author Cady, Sarah
dc.contributor.author Schmidt-Rohr, Klaus
dc.contributor.author Wang, Jun
dc.contributor.author Soto, Cinque
dc.contributor.author DeGrado, William
dc.contributor.author Hong, Mei
dc.contributor.department Chemistry
dc.date 2019-09-22T06:13:21.000
dc.date.accessioned 2020-06-30T01:16:57Z
dc.date.available 2020-06-30T01:16:57Z
dc.date.copyright Fri Jan 01 00:00:00 UTC 2010
dc.date.issued 2010-02-04
dc.description.abstract <p>The M2 protein of influenza A virus is a membrane-spanning tetrameric proton channel targeted by the antiviral drugs amantadine and rimantadine<a href="https://www.nature.com/articles/nature08722#ref-CR1" id="x-x-ref-link-section-d42326e395" title="Cady, S. D., Luo, W. B., Hu, F. & Hong, M. Structure and function of the influenza M2 proton channel. Biochemistry 48, 7356–7364 (2009)">1</a>. Resistance to these drugs has compromised their effectiveness against many influenza strains, including pandemic H1N1. A recent crystal structure of M2(22–46) showed electron densities attributed to a single amantadine in the amino-terminal half of the pore<a href="https://www.nature.com/articles/nature08722#ref-CR2" id="x-x-ref-link-section-d42326e399" title="Stouffer, A. L. et al. Structural basis for the function and inhibition of an influenza virus proton channel. Nature 451, 596–599 (2008)">2</a>, indicating a physical occlusion mechanism for inhibition. However, a solution NMR structure of M2(18–60) showed four rimantadines bound to the carboxy-terminal lipid-facing surface of the helices<a href="https://www.nature.com/articles/nature08722#ref-CR3" id="x-x-ref-link-section-d42326e403" title="Schnell, J. R. & Chou, J. J. Structure and mechanism of the M2 proton channel of influenza A virus. Nature 451, 591–595 (2008)">3</a>, suggesting an allosteric mechanism. Here we show by solid-state NMR spectroscopy that two amantadine-binding sites exist in M2 in phospholipid bilayers. The high-affinity site, occupied by a single amantadine, is located in the N-terminal channel lumen, surrounded by residues mutated in amantadine-resistant viruses. Quantification of the protein–amantadine distances resulted in a 0.3 Å-resolution structure of the high-affinity binding site. The second, low-affinity, site was observed on the C-terminal protein surface, but only when the drug reaches high concentrations in the bilayer. The orientation and dynamics of the drug are distinct in the two sites, as shown by 2H NMR. These results indicate that amantadine physically occludes the M2 channel, thus paving the way for developing new antiviral drugs against influenza viruses. The study demonstrates the ability of solid-state NMR to elucidate small-molecule interactions with membrane proteins and determine high-resolution structures of their complexes.</p>
dc.description.comments <p>This is a post-peer-review, pre-copyedit version of an article published in <em>Nature</em>. The final authenticated version is available online at: http://dx.doi.org/<a href="http://dx.doi.org/10.1038/nature08722" target="_blank">10.1038/nature08722</a>. Posted with permission.</p>
dc.format.mimetype application/pdf
dc.identifier archive/lib.dr.iastate.edu/chem_pubs/1143/
dc.identifier.articleid 2149
dc.identifier.contextkey 15332800
dc.identifier.s3bucket isulib-bepress-aws-west
dc.identifier.submissionpath chem_pubs/1143
dc.identifier.uri https://dr.lib.iastate.edu/handle/20.500.12876/14449
dc.language.iso en
dc.source.bitstream archive/lib.dr.iastate.edu/chem_pubs/1143/2010_CadySarah_StructureAmantadine.pdf|||Fri Jan 14 18:50:08 UTC 2022
dc.source.uri 10.1038/nature08722
dc.subject.disciplines Medicinal-Pharmaceutical Chemistry
dc.subject.disciplines Membrane Science
dc.title Structure of the amantadine binding site of influenza M2 proton channels in lipid bilayers
dc.type article
dc.type.genre article
dspace.entity.type Publication
relation.isAuthorOfPublication bdd61196-0f0a-4ec2-9723-b7edddf99843
relation.isOrgUnitOfPublication 42864f6e-7a3d-4be3-8b5a-0ae3c3830a11
File
Original bundle
Now showing 1 - 1 of 1
Name:
2010_CadySarah_StructureAmantadine.pdf
Size:
3.41 MB
Format:
Adobe Portable Document Format
Description:
Download
Collections
Publications