2ly0: Difference between revisions
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<StructureSection load='2ly0' size='340' side='right'caption='[[2ly0]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''> | <StructureSection load='2ly0' size='340' side='right'caption='[[2ly0]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2ly0]] is a 4 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2LY0 OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[2ly0]] is a 4 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2LY0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2LY0 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A2Y:(3S,5S,7S)-N-{[5-(THIOPHEN-2-YL)-1,2-OXAZOL-3-YL]METHYL}TRICYCLO[3.3.1.1~3,7~]DECAN-1-AMINIUM'>A2Y</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A2Y:(3S,5S,7S)-N-{[5-(THIOPHEN-2-YL)-1,2-OXAZOL-3-YL]METHYL}TRICYCLO[3.3.1.1~3,7~]DECAN-1-AMINIUM'>A2Y</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2ly0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ly0 OCA], [https://pdbe.org/2ly0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ly0 RCSB], [https://www.ebi.ac.uk/pdbsum/2ly0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ly0 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[[ | [[https://www.uniprot.org/uniprot/Q6XT21_9INFA Q6XT21_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.[SAAS:SAAS00108379] | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
Revision as of 14:30, 16 February 2022
Solution NMR structure of the influenza A virus S31N mutant (19-49) in presence of drug M2WJ332Solution NMR structure of the influenza A virus S31N mutant (19-49) in presence of drug M2WJ332
Structural highlights
Function[Q6XT21_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.[SAAS:SAAS00108379] Publication Abstract from PubMedThe influenza A virus M2 proton channel (A/M2) is the target of the antiviral drugs amantadine and rimantadine, whose use has been discontinued due to widespread drug resistance. Among the handful of drug-resistant mutants, S31N is found in more than 95% of the currently circulating viruses and shows greatly decreased inhibition by amantadine. The discovery of inhibitors of S31N has been hampered by the limited size, polarity, and dynamic nature of its amantadine-binding site. Nevertheless, we have discovered small-molecule drugs that inhibit S31N with potencies greater than amantadine's potency against WT M2. Drug binding locks the protein into a well-defined conformation, and the NMR structure of the complex shows the drug bound in the homotetrameric channel, threaded between the side chains of Asn31. Unrestrained molecular dynamics simulations predicted the same binding site. This S31N inhibitor, like other potent M2 inhibitors, contains a charged ammonium group. The ammonium binds as a hydrate to one of three sites aligned along the central cavity that appear to be hotspots for inhibition. These sites might stabilize hydronium-like species formed as protons diffuse through the outer channel to the proton-shuttling residue His37 near the cytoplasmic end of the channel. Structure and inhibition of the drug-resistant S31N mutant of the M2 ion channel of influenza A virus.,Wang J, Wu Y, Ma C, Fiorin G, Wang J, Pinto LH, Lamb RA, Klein ML, Degrado WF Proc Natl Acad Sci U S A. 2013 Jan 9. PMID:23302696[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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