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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
7178
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pubmed:dateCreated |
2008-1-31
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pubmed:databankReference |
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pubmed:abstractText |
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 pK(a) of the critical His residue. The structure provides a starting point for solving the problem of resistance to M2-channel blockers.
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
1476-4687
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
31
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pubmed:volume |
451
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
596-9
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pubmed:dateRevised |
2008-4-21
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pubmed:meshHeading |
pubmed-meshheading:18235504-Amantadine,
pubmed-meshheading:18235504-Crystallography, X-Ray,
pubmed-meshheading:18235504-Drug Resistance, Viral,
pubmed-meshheading:18235504-Histidine,
pubmed-meshheading:18235504-Hydrogen-Ion Concentration,
pubmed-meshheading:18235504-Influenza A virus,
pubmed-meshheading:18235504-Ion Channel Gating,
pubmed-meshheading:18235504-Models, Molecular,
pubmed-meshheading:18235504-Protein Structure, Quaternary,
pubmed-meshheading:18235504-Protons,
pubmed-meshheading:18235504-Structure-Activity Relationship,
pubmed-meshheading:18235504-Tryptophan,
pubmed-meshheading:18235504-Viral Matrix Proteins
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pubmed:year |
2008
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pubmed:articleTitle |
Structural basis for the function and inhibition of an influenza virus proton channel.
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pubmed:affiliation |
Department of Biochemistry and Biophysics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, Non-P.H.S.,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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