{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T09:48:48Z","timestamp":1790934528707,"version":"4.1.0"},"reference-count":50,"publisher":"National Academy of Sciences","issue":"5","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2008,2,5]]},"abstract":"<jats:p>\n                    The M2 protein of influenza A virus forms a transmembrane proton channel important for viral infection and replication. Amantadine blocks this channel, thus inhibiting viral replication. Elucidating the high-resolution structure of the M2 protein and its change upon amantadine binding is crucial for designing antiviral drugs to combat the growing resistance of influenza A viruses against amantadine. We used magic-angle-spinning solid-state NMR to determine the conformation and dynamics of the transmembrane domain of the protein M2TMP in the apo- and amantadine-bound states in lipid bilayers.\n                    <jats:sup>13<\/jats:sup>\n                    C chemical shifts and torsion angles of the protein in 1,2-dilauroyl-\n                    <jats:italic>sn<\/jats:italic>\n                    -glycero-3-phosphatidylcholine (DLPC) bilayers indicate that M2TMP is \u03b1-helical in both states, but the average conformation differs subtly, especially at the G34\u2013I35 linkage and V27 side chain. In the liquid-crystalline membrane, the complexed M2TMP shows dramatically narrower lines than the apo peptide. Analysis of the homogeneous and inhomogeneous line widths indicates that the apo-M2TMP undergoes significant microsecond-time scale motion, and amantadine binding alters the motional rates, causing line-narrowing. Amantadine also reduces the conformational heterogeneity of specific residues, including the G34\/I35 pair and several side chains. Finally, amantadine causes the helical segment N-terminal to G34 to increase its tilt angle by 3\u00b0, and the G34\u2013I35 torsion angles cause a kink of 5\u00b0 in the amantadine-bound helix. These data indicate that amantadine affects the M2 proton channel mainly by changing the distribution and exchange rates among multiple low-energy conformations and only subtly alters the average conformation and orientation. Amantadine-resistant mutations thus may arise from binding-incompetent changes in the conformational equilibrium.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0711500105","type":"journal-article","created":{"date-parts":[[2008,1,30]],"date-time":"2008-01-30T00:09:44Z","timestamp":1201651784000},"page":"1483-1488","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":108,"title":["Amantadine-induced conformational and dynamical changes of the influenza M2 transmembrane proton channel"],"prefix":"10.1073","volume":"105","author":[{"given":"Sarah D.","family":"Cady","sequence":"first","affiliation":[{"name":"Department of Chemistry, Iowa State University, Ames, IA 50011"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Iowa State University, Ames, IA 50011"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2008,2,5]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90452-I"},{"key":"e_1_3_3_2_2","first-page":"18","article-title":"Controlling influenza virus replication by inhibiting its proton flow.","volume":"3","author":"Pinto LH","year":"2007","unstructured":"LH Pinto, RA Lamb, Controlling influenza virus replication by inhibiting its proton flow. 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