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Structural basis for the function and inhibition of an influenza virus proton channel.

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Title: Structural basis for the function and inhibition of an influenza virus proton channel.
Authors: Stouffer, Amanda L., Acharya, Rudresh, Salom, David, Levine, Anna S., Di Costanzo, Luigi, Soto, Cinque S., Tereshko, Valentina, Nanda, Vikas, Stayrook, Steven, DeGrado, William F.
Source: Nature. 1/31/2008, Vol. 451 Issue 7178, p596-599. 4p. 4 Diagrams.
Subjects: Influenza A virus, Protons, Acidification, Endosomes, Amantadine, Protein binding, Antibiotic residues
Abstract: The M2 protein from influenza A virus is a pH-activated proton channel that mediates acidification of the interior of viral particles entrapped in endosomes. M2 is the target of the anti-influenza drugs amantadine and rimantadine; recently, resistance to these drugs in humans, birds and pigs has reached more than 90% (ref. 1). Here we describe the crystal structure of the transmembrane-spanning region of the homotetrameric protein in the presence and absence of the channel-blocking drug amantadine. pH-dependent structural changes occur near a set of conserved His and Trp residues that are involved in proton gating. The drug-binding site is lined by residues that are mutated in amantadine-resistant viruses. Binding of amantadine physically occludes the pore, and might also perturb the pKa of the critical His residue. The structure provides a starting point for solving the problem of resistance to M2-channel blockers. [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
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  Data: Structural basis for the function and inhibition of an influenza virus proton channel.
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  Data: <searchLink fieldCode="JN" term="%22Nature%22">Nature</searchLink>. 1/31/2008, Vol. 451 Issue 7178, p596-599. 4p. 4 Diagrams.
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  Data: <searchLink fieldCode="DE" term="%22Influenza+A+virus%22">Influenza A virus</searchLink><br /><searchLink fieldCode="DE" term="%22Protons%22">Protons</searchLink><br /><searchLink fieldCode="DE" term="%22Acidification%22">Acidification</searchLink><br /><searchLink fieldCode="DE" term="%22Endosomes%22">Endosomes</searchLink><br /><searchLink fieldCode="DE" term="%22Amantadine%22">Amantadine</searchLink><br /><searchLink fieldCode="DE" term="%22Protein+binding%22">Protein binding</searchLink><br /><searchLink fieldCode="DE" term="%22Antibiotic+residues%22">Antibiotic residues</searchLink>
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  Data: The M2 protein from influenza A virus is a pH-activated proton channel that mediates acidification of the interior of viral particles entrapped in endosomes. M2 is the target of the anti-influenza drugs amantadine and rimantadine; recently, resistance to these drugs in humans, birds and pigs has reached more than 90% (ref. 1). Here we describe the crystal structure of the transmembrane-spanning region of the homotetrameric protein in the presence and absence of the channel-blocking drug amantadine. pH-dependent structural changes occur near a set of conserved His and Trp residues that are involved in proton gating. The drug-binding site is lined by residues that are mutated in amantadine-resistant viruses. Binding of amantadine physically occludes the pore, and might also perturb the pKa of the critical His residue. The structure provides a starting point for solving the problem of resistance to M2-channel blockers. [ABSTRACT FROM AUTHOR]
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  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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              Text: 1/31/2008
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