M2 Proton Channel: Difference between revisions
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{{STRUCTURE_1nyj | PDB=1nyj | SCENE=User:Sarah_Henke/Sandbox_1/M2_Channel/1}} | {{STRUCTURE_1nyj | PDB=1nyj | SCENE=User:Sarah_Henke/Sandbox_1/M2_Channel/1}} | ||
== M2 Proton Channel from ''Influenza'' A Virus == | == M2 Proton Channel from ''Influenza'' A Virus == | ||
== Background == | == Background == | ||
The M2 proton channel is a key protein that leads to viral infection.<ref name="Takeuchi" /> The M2 proton channel acidifies the virion which allows the viral matrix protein (M1) to disassociate from the ribonucleoprotein (RNP).<ref name="Wu">PMID:12972147 </ref> This allows the RNP to be transported to the nucleus of the cell.<ref name="Wu" /> Several recent studies have looked at the effects of <scene name='User:Sarah_Henke/Sandbox_1/Amantadine/1'>amantadine</scene><ref name="Stouffer">PMID:18235504 </ref> and <scene name='User:Sarah_Henke/Sandbox_1/Rimantadine/1'>rimantadine</scene><ref name="Schnell">PMID:18235503 </ref> on inhibiting the transfer of protons through the M2 channel.<ref name="Stouffer" /> Amantadine is a proton surrogate that competes with protons for binding to His37, the residue involved in the gating mechanism.<ref name="Lear" /> It has been found that M2 is resistant to these two drugs in 90% of humans, birds and pigs.<ref name="Stouffer" /> Understanding the structure and function of this proton channel is necessary in solving the resistance problem.<ref name="Stouffer" /> | The M2 proton channel is a key protein that leads to viral infection.<ref name="Takeuchi" /> The M2 proton channel acidifies the virion which allows the viral matrix protein (M1) to disassociate from the ribonucleoprotein (RNP).<ref name="Wu">PMID:12972147 </ref> This allows the RNP to be transported to the nucleus of the cell.<ref name="Wu" /> Several recent studies have looked at the effects of <scene name='User:Sarah_Henke/Sandbox_1/Amantadine/1'>amantadine</scene><ref name="Stouffer">PMID:18235504 </ref> and <scene name='User:Sarah_Henke/Sandbox_1/Rimantadine/1'>rimantadine</scene><ref name="Schnell">PMID:18235503 </ref> on inhibiting the transfer of protons through the M2 channel.<ref name="Stouffer" /> Amantadine is a proton surrogate that competes with protons for binding to His37, the residue involved in the gating mechanism.<ref name="Lear" /> It has been found that M2 is resistant to these two drugs in 90% of humans, birds and pigs.<ref name="Stouffer" /> Understanding the structure and function of this proton channel is necessary in solving the resistance problem.<ref name="Stouffer" /> | ||
<applet load='1nyj' size='300' frame='true' align='right' caption='The closed state structure of M2 protein H+ channel by solid state NMR spectroscopy. [Stouffer et al, 2008]' /> | |||
== Structure == | == Structure == | ||
The M2 proton channel from influenza A is 97 amino acid residues and forms a 24-residue N-terminal extracellular domain, a 19-residue trans-membrane domain, and a 54-residue C-terminal cytoplasmic domain.<ref name="Wu" /> The 19-residue TM domain forms the highly selective proton channel.<ref name="Takeuchi">PMID:12972149 </ref> Circular dichroism spectra has shown the TM domain to form an <scene name='User:Sarah_Henke/Sandbox_1/Momomer/2'>α-helix</scene> that spans the membrane.<ref name="Wu" /> By analytical ultracentrifugation, the TM domain is found to form <scene name='User:Sarah_Henke/Sandbox_1/Alpha_hlix/1'>homotetramers</scene> which contains four identical α-helices.<ref name="Takeuchi" /> Secondary structure is color coded by the following, if present: {{Template:ColorKey_Helix}}, {{Template:ColorKey_Strand}}, and {{Template:ColorKey_Turn}}. When viewed in the <scene name='User:Sarah_Henke/Sandbox_1/N_to_c/1'>N->C color coding</scene> the <FONT COLOR="blue">'''N-terminus'''</FONT> (see scale below) is located near the external side of the membrane while the <FONT COLOR="red">'''C-terminus'''</FONT> is located near the internal side of the membrane, closest to the virion. This tetrameric bundle of the TM domain is found by NMR to be tilted by 25-38° from the channel axis.<ref name="Takeuchi" /> The tetrameric helices form a left-handed bundle that resembles a truncated cone.<ref name="Stouffer" /> The TM helicies are arranged around the channel pore with an approximate four-fold rotational symmetry.<ref name="Takeuchi" /> | The M2 proton channel from influenza A is 97 amino acid residues and forms a 24-residue N-terminal extracellular domain, a 19-residue trans-membrane domain, and a 54-residue C-terminal cytoplasmic domain.<ref name="Wu" /> The 19-residue TM domain forms the highly selective proton channel.<ref name="Takeuchi">PMID:12972149 </ref> Circular dichroism spectra has shown the TM domain to form an <scene name='User:Sarah_Henke/Sandbox_1/Momomer/2'>α-helix</scene> that spans the membrane.<ref name="Wu" /> By analytical ultracentrifugation, the TM domain is found to form <scene name='User:Sarah_Henke/Sandbox_1/Alpha_hlix/1'>homotetramers</scene> which contains four identical α-helices.<ref name="Takeuchi" /> Secondary structure is color coded by the following, if present: {{Template:ColorKey_Helix}}, {{Template:ColorKey_Strand}}, and {{Template:ColorKey_Turn}}. When viewed in the <scene name='User:Sarah_Henke/Sandbox_1/N_to_c/1'>N->C color coding</scene> the <FONT COLOR="blue">'''N-terminus'''</FONT> (see scale below) is located near the external side of the membrane while the <FONT COLOR="red">'''C-terminus'''</FONT> is located near the internal side of the membrane, closest to the virion. This tetrameric bundle of the TM domain is found by NMR to be tilted by 25-38° from the channel axis.<ref name="Takeuchi" /> The tetrameric helices form a left-handed bundle that resembles a truncated cone.<ref name="Stouffer" /> The TM helicies are arranged around the channel pore with an approximate four-fold rotational symmetry.<ref name="Takeuchi" /> | ||