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| <table style="background-color:#ffffc0" cellpadding="8" width="95%" border="0"><tr><td>Please do NOT make changes to this Sandbox until after May 15 2011. </td></tr> | | <StructureSection load='' size='340' side='right' caption='' scene='75/751104/L22s/3' pspeed='8'> |
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| | | <jmol> |
| <Structure load='2KQT ' size='500' frame='true' align='right' caption='M2 transmembrane peptide of the influenza A virus in DMPC lipid bilayers bound to deuterated amantadine' scene='Opening View' />
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| | | <script> |
| '''Introduction'''
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| Influenza A, better known as the flu, an infection of the nose, throat, and lungs caused by the influenza virus. Basic symptoms include aches, chills, fever, loss of energy and dizziness, but complications can include pneumonia, encephalitis, bronchitis, and death—about 36,000 people every year die of complications from the flu (CDC).
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| | | <text>Wild type conformation,</text> |
| The M2 protein is a proton-selective ion channel protein that plays an important role in the life cycle of the influenza A virus. The channel itself is a homotetramer with four identical M2 units, where each M2 protein is a helix stabilized by two disulfide bonds. At a low pH, the channel allows hydrogen ions to enter the viral particle form the endosome, effectively lowering the pH on the interior of the virus. This in turn causes the dissociation of the viral matrix protein M1 from the ribonucleoprotein, a critical step in “uncoating” the virus to introduce its contents to the cytoplasm of the host cell (Stouffer). The M2 protein itself consists of three major protein domains: a stretch of 24 amino acids on the N-terminal end that are exposed to the external environment, 22 (largely hydrophobic) amino acids in the transmembrane region, and 52 amino acids on the C-terminal end which are exposed to the inside of the viral particle (Schnell).
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| | | </jmol> |
| The function of the M2 channel can be inhibited by the antiviral drug Amantadine, an inhibition that effectively blocks the virus from taking over the host cell. Amantadine inhibits the replication of influenza A viruses by interfering with the uncoating of the virus within the cell. Amantadine is an M2 inhibitor that blocks the ion channel formed by the M2 protein that spans the viral membrane. By blocking this channel, Amantadine effectively prevents the acidification and subsequent release of viral elements into the host cell. Unfortunately, the M2 gene is susceptible to mutations. When one of five (of the 22) amino acids in the transmembrane region is suitably substituted, Amantadine no longer binds in such a way that would block the motion of the protons into the virus. As of 2009, the CDC noted that a full 100% of Influenza A viruses of types H3N2 and 2009 pandemic flu samples cultured in the United States showed a resistance to Amantadine (CDC).
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| '''Overall Structure'''
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| | | <jmolLink> |
| '''Drug Binding Site'''
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| '''Additional Features'''
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| | | <text>Mutation |
| '''Credits'''
| | </text> |
| | | </jmolLink> |
| Introduction -- Josephine Harrington
| | </jmol> |
| | | Click here to see the |
| Overall structure -- Andrea Simoni
| | <jmol> |
| | | <jmolLink> |
| Drug binding site -- Joshua Drolet
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| Additional features -- John Hickey
| | </script> |
| | | <text>Mutated and wildtype residues |
| '''References'''
| | </text> |
| Cady, S.D., Schmidt-Rohr, K., Wang, J., Soto, C., DeGrado, W.F., Hong, M. "Structure of the amantadine binding site of influenza M2 proton channels in lipid bilayers," (2010) ''Nature'' '''463''': 689-692.
| | </jmolLink> |
| | | </jmol> together. Click here to |
| Stouffer AL, Acharya R, Salom D, Levine AS, Di Costanzo L, Soto CS, Tereshko V, Nanda V, Stayrook S, DeGrado WF (2008). "Structural basis for the function and inhibition of an influenza virus proton channel". Nature 451 (7178): 596-9
| | <jmol> |
| | | <jmolLink> |
| Schnell JR, Chou JJ (2008). "Structure and mechanism of the M2 proton channel of influenza A virus". Nature 451 (7178): 591–5.
| | <script> |
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| Pielak RM, Schnell JR, Chou JJ: Mechanism of drug inhibition and drug resistance of influenza A M2 channel. Proc Natl Acad Sci, 106(18):7379-84 (2009).
| | </script> |
| | | <text>see animation |
| "CDC Recommends against the Use of Amantadine and Rimantadine for the Treatment or Prophylaxis of Influenza in the United States during the 2005–06 Influenza Season". CDC Health Alert. Centers for Disease Control and Prevention
| | </text> |
| | | </jmolLink> |
| Hay AJ, Wolstenholme AJ, Skehel JJ, Smith MH. The molecular basis of the specific anti-influenza action of amantadine. EMBO J 1985; 4: 3021-4.
| | </jmol> of both states. Putative new hydrogen bonds were added. |
| | | </StructureSection> |
| Stephenson I, Nicholson KG. Influenza: vaccination and treatment. Eur Respir J 2001; 17: 1282-93.
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