2kqt: Difference between revisions

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 ==Solid-state NMR structure of the M2 transmembrane peptide of the influenza A virus in DMPC lipid bilayers bound to deuterated amantadine==
-<StructureSection load='2kqt' size='340' side='right'caption='[[2kqt]], [[NMR_Ensembles_of_Models | 17 NMR models]]' scene=''>
+<StructureSection load='2kqt' size='340' side='right'caption='[[2kqt]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2kqt]] is a 4 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2KQT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2KQT FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2kqt]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Influenza_A_virus_H3N2 Influenza A virus H3N2]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2KQT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2KQT FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=308:(3S,5S,7S)-TRICYCLO[3.3.1.1~3,7~]DECAN-1-AMINE'>308</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2kad|2kad]], [[2h95|2h95]], [[2rlf|2rlf]], [[3c9j|3c9j]], [[1nyj|1nyj]], [[3bkd|3bkd]]</div></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2kqt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2kqt OCA], [https://pdbe.org/2kqt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2kqt RCSB], [https://www.ebi.ac.uk/pdbsum/2kqt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2kqt ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/Q9YP62_9INFA Q9YP62_9INFA]] Forms a proton-selective ion channel that is necessary for the efficient release of the viral genome during virus entry. After attaching to the cell surface, the virion enters the cell by endocytosis. Acidification of the endosome triggers M2 ion channel activity. The influx of protons into virion interior is believed to disrupt interactions between the viral ribonucleoprotein (RNP), matrix protein 1 (M1), and lipid bilayers, thereby freeing the viral genome from interaction with viral proteins and enabling RNA segments to migrate to the host cell nucleus, where influenza virus RNA transcription and replication occur. Also plays a role in viral proteins secretory pathway. Elevates the intravesicular pH of normally acidic compartments, such as trans-Golgi network, preventing newly formed hemagglutinin from premature switching to the fusion-active conformation (By similarity).[SAAS:SAAS002089_004_400258]
+[https://www.uniprot.org/uniprot/M2_I97A1 M2_I97A1] Forms a proton-selective ion channel that is necessary for the efficient release of the viral genome during virus entry. After attaching to the cell surface, the virion enters the cell by endocytosis. Acidification of the endosome triggers M2 ion channel activity. The influx of protons into virion interior is believed to disrupt interactions between the viral ribonucleoprotein (RNP), matrix protein 1 (M1), and lipid bilayers, thereby freeing the viral genome from interaction with viral proteins and enabling RNA segments to migrate to the host cell nucleus, where influenza virus RNA transcription and replication occur. Also plays a role in viral proteins secretory pathway. Elevates the intravesicular pH of normally acidic compartments, such as trans-Golgi network, preventing newly formed hemagglutinin from premature switching to the fusion-active conformation.
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
-Amantadine is known to block the M2 proton channel of the Influenza A virus. Here, we present a structure of the M2 trans-membrane domain blocked with amantadine, built using orientational constraints obtained from solid-state NMR polarization-inversion-spin-exchange-at-the-magic-angle experiments. The data indicates a kink in the monomer between two helical fragments having 20 degrees and 31 degrees tilt angles with respect to the membrane normal. This monomer structure is then used to construct a plausible model of the tetrameric amantadine-blocked M2 trans-membrane channel. The influence of amantadine binding through comparative cross polarization magic-angle spinning spectra was also observed. In addition, spectra are shown of the amantadine-resistant mutant, S31N, in the presence and absence of amantadine.
+The M2 protein of influenza A virus is a membrane-spanning tetrameric proton channel targeted by the antiviral drugs amantadine and rimantadine. Resistance to these drugs has compromised their effectiveness against many influenza strains, including pandemic H1N1. A recent crystal structure of M2(22-46) showed electron densities attributed to a single amantadine in the amino-terminal half of the pore, indicating a physical occlusion mechanism for inhibition. However, a solution NMR structure of M2(18-60) showed four rimantadines bound to the carboxy-terminal lipid-facing surface of the helices, suggesting an allosteric mechanism. Here we show by solid-state NMR spectroscopy that two amantadine-binding sites exist in M2 in phospholipid bilayers. The high-affinity site, occupied by a single amantadine, is located in the N-terminal channel lumen, surrounded by residues mutated in amantadine-resistant viruses. Quantification of the protein-amantadine distances resulted in a 0.3 A-resolution structure of the high-affinity binding site. The second, low-affinity, site was observed on the C-terminal protein surface, but only when the drug reaches high concentrations in the bilayer. The orientation and dynamics of the drug are distinct in the two sites, as shown by (2)H NMR. These results indicate that amantadine physically occludes the M2 channel, thus paving the way for developing new antiviral drugs against influenza viruses. The study demonstrates the ability of solid-state NMR to elucidate small-molecule interactions with membrane proteins and determine high-resolution structures of their complexes.
-Backbone structure of the amantadine-blocked trans-membrane domain M2 proton channel from Influenza A virus.,Hu J, Asbury T, Achuthan S, Li C, Bertram R, Quine JR, Fu R, Cross TA Biophys J. 2007 Jun 15;92(12):4335-43. Epub 2007 Mar 23. PMID:17384070<ref>PMID:17384070</ref>
+Structure of the amantadine binding site of influenza M2 proton channels in lipid bilayers.,Cady SD, Schmidt-Rohr K, Wang J, Soto CS, Degrado WF, Hong M Nature. 2010 Feb 4;463(7281):689-92. PMID:20130653<ref>PMID:20130653</ref>
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
@@ Line 27: / Line 26: @@
 __TOC__
 </StructureSection>
+[[Category: Influenza A virus H3N2]]
 [[Category: Large Structures]]
-[[Category: Cady, S D]]
+[[Category: Cady SD]]
-[[Category: DeGrado, W F]]
+[[Category: DeGrado WF]]
-[[Category: Hong, M]]
+[[Category: Hong M]]
-[[Category: Schmidt-Rohr, K]]
+[[Category: Schmidt-Rohr K]]
-[[Category: Soto, C S]]
+[[Category: Soto CS]]
-[[Category: Wang, J]]
+[[Category: Wang J]]
-[[Category: Amantadine]]
-[[Category: Influenza]]
-[[Category: Redor]]
-[[Category: Transmembrane]]
-[[Category: Transport protein]]