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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'> |
| | | The scene loads with the |
| | | <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' />
| | <jmolLink> |
| | | <script> |
| '''Introduction'''
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| | | </script> |
| 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).
| | <text>Wild type conformation,</text> |
| | | </jmolLink> |
| 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). | | </jmol> |
| | | and this renders the |
| 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).
| | <jmol> |
| | | <jmolLink> |
| '''Overall Structure'''
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| '''Drug Binding Site'''
| | </script> |
| | | <text>Mutation |
| Amantadine binds with high affinity to a site in the M2 protein spanning five residues: Leu 26, Val 27, Ala 30, Ser 31, and Gly 34. This high affinity is seen at pH’s closer to neutral. In lower pH’s the protein is only somewhat bound to amantadine. Therefore, when determining the mechanism by which amantadine blocks the channel experiments must be conducted at neutral pH. <scene name='Sandbox_111/Binding/10'>Binding of amantadine</scene> to the M2 protein is illustrated for viewing of the bonds that form.
| | </text> |
| | | </jmolLink> |
| '''Additional Features'''
| | </jmol> |
| | | Click here to see the |
| '''Credits'''
| | <jmol> |
| | | <jmolLink> |
| Introduction -- Josephine Harrington
| | <script> |
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| Overall structure -- Andrea Simoni
| | </script> |
| | | <text>Mutated and wildtype residues |
| Drug binding site -- Joshua Drolet
| | </text> |
| | | </jmolLink> |
| Additional features -- John Hickey
| | </jmol> together. Click here to |
| | | <jmol> |
| '''References'''
| | <jmolLink> |
| | | <script> |
| 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.
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| | | </script> |
| 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
| | <text>see animation |
| | | </text> |
| Schnell JR, Chou JJ (2008). "Structure and mechanism of the M2 proton channel of influenza A virus". Nature 451 (7178): 591–5.
| | </jmolLink> |
| | | </jmol> of both states. Putative new hydrogen bonds were added. |
| 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).
| | </StructureSection> |
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| "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
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| 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.
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| Stephenson I, Nicholson KG. Influenza: vaccination and treatment. Eur Respir J 2001; 17: 1282-93.
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