Structure of the amantadine binding site of influenza M2 proton channels in lipid bilayers.
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| Title: | Structure of the amantadine binding site of influenza M2 proton channels in lipid bilayers. |
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| Authors: | Cady, Sarah D., Schmidt-Rohr, Klaus, Jun Wang, Soto, Cinque S., DeGrado, William F., Mei Hong |
| Source: | Nature. 2/4/2010, Vol. 463 Issue 7281, p689-692. 4p. 2 Diagrams, 3 Graphs. |
| Subjects: | Amantadine, Influenza A virus, Bilayer lipid membranes, Antiviral agents, Nuclear magnetic resonance spectroscopy, Influenza A virus, H1N1 subtype, Allosteric regulation, Biological membranes, Membrane proteins |
| Abstract: | The M2 protein of influenza A virus is a membrane-spanning tetrameric proton channel targeted by the antiviral drugs amantadine and rimantadine. 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, 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, 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. [ABSTRACT FROM AUTHOR] |
| Copyright of Nature is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Psychology and Behavioral Sciences Collection |
| FullText | Links: – Type: pdflink Text: Availability: 0 |
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| Header | DbId: pbh DbLabel: Psychology and Behavioral Sciences Collection An: 47864492 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: Structure of the amantadine binding site of influenza M2 proton channels in lipid bilayers. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Cady%2C+Sarah+D%2E%22">Cady, Sarah D.</searchLink><br /><searchLink fieldCode="AR" term="%22Schmidt-Rohr%2C+Klaus%22">Schmidt-Rohr, Klaus</searchLink><br /><searchLink fieldCode="AR" term="%22Jun+Wang%22">Jun Wang</searchLink><br /><searchLink fieldCode="AR" term="%22Soto%2C+Cinque+S%2E%22">Soto, Cinque S.</searchLink><br /><searchLink fieldCode="AR" term="%22DeGrado%2C+William+F%2E%22">DeGrado, William F.</searchLink><br /><searchLink fieldCode="AR" term="%22Mei+Hong%22">Mei Hong</searchLink> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Nature%22">Nature</searchLink>. 2/4/2010, Vol. 463 Issue 7281, p689-692. 4p. 2 Diagrams, 3 Graphs. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Amantadine%22">Amantadine</searchLink><br /><searchLink fieldCode="DE" term="%22Influenza+A+virus%22">Influenza A virus</searchLink><br /><searchLink fieldCode="DE" term="%22Bilayer+lipid+membranes%22">Bilayer lipid membranes</searchLink><br /><searchLink fieldCode="DE" term="%22Antiviral+agents%22">Antiviral agents</searchLink><br /><searchLink fieldCode="DE" term="%22Nuclear+magnetic+resonance+spectroscopy%22">Nuclear magnetic resonance spectroscopy</searchLink><br /><searchLink fieldCode="DE" term="%22Influenza+A+virus%2C+H1N1+subtype%22">Influenza A virus, H1N1 subtype</searchLink><br /><searchLink fieldCode="DE" term="%22Allosteric+regulation%22">Allosteric regulation</searchLink><br /><searchLink fieldCode="DE" term="%22Biological+membranes%22">Biological membranes</searchLink><br /><searchLink fieldCode="DE" term="%22Membrane+proteins%22">Membrane proteins</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: The M2 protein of influenza A virus is a membrane-spanning tetrameric proton channel targeted by the antiviral drugs amantadine and rimantadine. 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, 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, 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. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Nature is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1038/nature08722 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 4 StartPage: 689 Subjects: – SubjectFull: Amantadine Type: general – SubjectFull: Influenza A virus Type: general – SubjectFull: Bilayer lipid membranes Type: general – SubjectFull: Antiviral agents Type: general – SubjectFull: Nuclear magnetic resonance spectroscopy Type: general – SubjectFull: Influenza A virus, H1N1 subtype Type: general – SubjectFull: Allosteric regulation Type: general – SubjectFull: Biological membranes Type: general – SubjectFull: Membrane proteins Type: general Titles: – TitleFull: Structure of the amantadine binding site of influenza M2 proton channels in lipid bilayers. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Cady, Sarah D. – PersonEntity: Name: NameFull: Schmidt-Rohr, Klaus – PersonEntity: Name: NameFull: Jun Wang – PersonEntity: Name: NameFull: Soto, Cinque S. – PersonEntity: Name: NameFull: DeGrado, William F. – PersonEntity: Name: NameFull: Mei Hong IsPartOfRelationships: – BibEntity: Dates: – D: 04 M: 02 Text: 2/4/2010 Type: published Y: 2010 Identifiers: – Type: issn-print Value: 00280836 Numbering: – Type: volume Value: 463 – Type: issue Value: 7281 Titles: – TitleFull: Nature Type: main |
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