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2KWX

The V27A mutant of influenza A M2 proton channel

Summary for 2KWX
Entry DOI10.2210/pdb2kwx/pdb
Related2KIH 2RLF
DescriptorMatrix protein 2 (1 entity in total)
Functional Keywordsm2 proton channel, influenza a, v27a resistant mutant, transport protein
Biological sourceInfluenza A virus
Cellular locationVirion membrane (By similarity): P63231
Total number of polymer chains4
Total formula weight17681.17
Authors
Pielak, R.M.,Chou, J.J. (deposition date: 2010-04-20, release date: 2010-09-29, Last modification date: 2024-05-22)
Primary citationPielak, R.M.,Chou, J.J.
Solution NMR structure of the V27A drug resistant mutant of influenza A M2 channel.
Biochem.Biophys.Res.Commun., 401:58-63, 2010
Cited by
PubMed Abstract: The M2 protein of influenza A virus forms a proton-selective channel that is required for viral replication. It is the target of the anti-influenza drugs, amantadine and rimantadine. Widespread drug resistant mutants, however, has greatly compromised the effectiveness of these drugs. Here, we report the solution NMR structure of the highly pathogenic, drug resistant mutant V27A. The structure reveals subtle structural differences from wildtype that maybe linked to drug resistance. The V27A mutation significantly decreases hydrophobic packing between the N-terminal ends of the transmembrane helices, which explains the looser, more dynamic tetrameric assembly. The weakened channel assembly can resist drug binding either by destabilizing the rimantadine-binding pocket at Asp44, in the case of the allosteric inhibition model, or by reducing hydrophobic contacts with amantadine in the pore, in the case of the pore-blocking model. Moreover, the V27A structure shows a substantially increased channel opening at the N-terminal end, which may explain the faster proton conduction observed for this mutant. Furthermore, due to the high quality NMR data recorded for the V27A mutant, we were able to determine the structured region connecting the channel domain to the C-terminal amphipathic helices that was not determined in the wildtype structure. The new structural data show that the amphipathic helices are packed much more closely to the channel domain and provide new insights into the proton transfer pathway.
PubMed: 20833142
DOI: 10.1016/j.bbrc.2010.09.008
PDB entries with the same primary citation
Experimental method
SOLUTION NMR
Structure validation

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