Magic Angle Spinning NMR Investigation of Influenza A M2(18-60): Support for an Allosteric Mechanism of Inhibition
The tetrameric M2 proton channel from influenza A virus conducts protons at low pH and is inhibited by aminoadamantyl drugs such as amantadine and rimantadine (Rmt). We report magic angle spinning NMR spectra of POPC and DPhPC membrane-embedded M2[subscript 18−60], both apo and in the presence of Rm...
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| Format: | Article |
| Language: | en_US |
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American Chemical Society (ACS)
2012
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| Online Access: | http://hdl.handle.net/1721.1/71972 https://orcid.org/0000-0002-3349-6212 https://orcid.org/0000-0003-1589-832X |
| _version_ | 1811087236410638336 |
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| author | Andreas, Loren Eddy, Matthew Thomas Pielak, Rafal M. Chou, James Griffin, Robert Guy |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Andreas, Loren Eddy, Matthew Thomas Pielak, Rafal M. Chou, James Griffin, Robert Guy |
| author_sort | Andreas, Loren |
| collection | MIT |
| description | The tetrameric M2 proton channel from influenza A virus conducts protons at low pH and is inhibited by aminoadamantyl drugs such as amantadine and rimantadine (Rmt). We report magic angle spinning NMR spectra of POPC and DPhPC membrane-embedded M2[subscript 18−60], both apo and in the presence of Rmt. Similar line widths in the spectra of apo and bound M2 indicate that Rmt does not have a significant impact on the dynamics or conformational heterogeneity of this construct. Substantial chemical shift changes for many residues in the transmembrane region support an allosteric mechanism of inhibition. An Rmt titration supports a binding stoichiometry of >1 Rmt molecule per channel and shows that nonspecific binding or changes in membrane composition are unlikely sources of the chemical shift changes. In addition, doubling of spectral lines in all of the observed samples provides evidence that the channel assembles with twofold symmetry. |
| first_indexed | 2024-09-23T13:42:14Z |
| format | Article |
| id | mit-1721.1/71972 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:42:14Z |
| publishDate | 2012 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/719722022-10-01T16:37:34Z Magic Angle Spinning NMR Investigation of Influenza A M2(18-60): Support for an Allosteric Mechanism of Inhibition Andreas, Loren Eddy, Matthew Thomas Pielak, Rafal M. Chou, James Griffin, Robert Guy Massachusetts Institute of Technology. Department of Chemistry Francis Bitter Magnet Laboratory (Massachusetts Institute of Technology) Griffin, Robert Guy Eddy, Matthew Thomas Griffin, Robert Guy Andreas, Loren The tetrameric M2 proton channel from influenza A virus conducts protons at low pH and is inhibited by aminoadamantyl drugs such as amantadine and rimantadine (Rmt). We report magic angle spinning NMR spectra of POPC and DPhPC membrane-embedded M2[subscript 18−60], both apo and in the presence of Rmt. Similar line widths in the spectra of apo and bound M2 indicate that Rmt does not have a significant impact on the dynamics or conformational heterogeneity of this construct. Substantial chemical shift changes for many residues in the transmembrane region support an allosteric mechanism of inhibition. An Rmt titration supports a binding stoichiometry of >1 Rmt molecule per channel and shows that nonspecific binding or changes in membrane composition are unlikely sources of the chemical shift changes. In addition, doubling of spectral lines in all of the observed samples provides evidence that the channel assembles with twofold symmetry. National Institutes of Health (U.S.) (EB001960) National Institutes of Health (U.S.) (EB002026) National Institutes of Health (U.S.) (Al067438) National Science Foundation (U.S.). Graduate Research Fellowship Program 2012-08-03T13:42:02Z 2012-08-03T13:42:02Z 2010-07 2010-02 Article http://purl.org/eprint/type/JournalArticle 0002-7863 1520-5126 http://hdl.handle.net/1721.1/71972 Andreas, Loren B. et al. “Magic Angle Spinning NMR Investigation of Influenza A M2[subscript 18−60]: Support for an Allosteric Mechanism of Inhibition.” Journal of the American Chemical Society 132.32 (2010): 10958–10960. https://orcid.org/0000-0002-3349-6212 https://orcid.org/0000-0003-1589-832X en_US http://dx.doi.org/10.1021/ja101537p Journal of the American Chemical Society Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Chemical Society (ACS) PMC |
| spellingShingle | Andreas, Loren Eddy, Matthew Thomas Pielak, Rafal M. Chou, James Griffin, Robert Guy Magic Angle Spinning NMR Investigation of Influenza A M2(18-60): Support for an Allosteric Mechanism of Inhibition |
| title | Magic Angle Spinning NMR Investigation of Influenza A M2(18-60): Support for an Allosteric Mechanism of Inhibition |
| title_full | Magic Angle Spinning NMR Investigation of Influenza A M2(18-60): Support for an Allosteric Mechanism of Inhibition |
| title_fullStr | Magic Angle Spinning NMR Investigation of Influenza A M2(18-60): Support for an Allosteric Mechanism of Inhibition |
| title_full_unstemmed | Magic Angle Spinning NMR Investigation of Influenza A M2(18-60): Support for an Allosteric Mechanism of Inhibition |
| title_short | Magic Angle Spinning NMR Investigation of Influenza A M2(18-60): Support for an Allosteric Mechanism of Inhibition |
| title_sort | magic angle spinning nmr investigation of influenza a m2 18 60 support for an allosteric mechanism of inhibition |
| url | http://hdl.handle.net/1721.1/71972 https://orcid.org/0000-0002-3349-6212 https://orcid.org/0000-0003-1589-832X |
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