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==Structure of drug-resistant V27A mutant of the influenza M2 proton channel bound to spiroadamantyl amine inhibitor, TM + cytosolic helix construct==
<StructureSection load='6oug' size='340' side='right'caption='[[6oug]], [[Resolution|resolution]] 3.01&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6oug]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Influenza_A_virus_(A/Memphis/1/1971(H3N2)) Influenza A virus (A/Memphis/1/1971(H3N2))]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6OUG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6OUG FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.01&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=E01:(1r,1S,3S,5S,7S)-spiro[cyclohexane-1,2-tricyclo[3.3.1.1~3,7~]decan]-4-amine'>E01</scene></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=6oug FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6oug OCA], [https://pdbe.org/6oug PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6oug RCSB], [https://www.ebi.ac.uk/pdbsum/6oug PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6oug ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/M2_I71A1 M2_I71A1] 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.
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== Publication Abstract from PubMed ==
The V27A mutation confers adamantane resistance on the influenza A matrix 2 (M2) proton channel and is becoming more prevalent in circulating populations of influenza A virus. We have used X-ray crystallography to determine structures of a spiro-adamantyl amine inhibitor bound to M2(22-46) V27A and also to M2(21-61) V27A in the Inwardclosed conformation. The spiro-adamantyl amine binding site is nearly identical for the two crystal structures. Compared to the M2 "wild type" (WT) with valine at position 27, we observe that the channel pore is wider at its N-terminus as a result of the V27A mutation and that this removes V27 side chain hydrophobic interactions that are important for binding of amantadine and rimantadine. The spiro-adamantyl amine inhibitor blocks proton conductance in the WT and V27A mutant channels by shifting its binding site in the pore depending on which residue is present at position 27. Additionally, in the structure of the M2(21-61) V27A construct, the C-terminus of the channel is tightly packed relative to that of the M2(22-46) construct. We observe that residues Asp44, Arg45, and Phe48 face the center of the channel pore and would be well-positioned to interact with protons exiting the M2 channel after passing through the His37 gate. A 300 ns molecular dynamics simulation of the M2(22-46) V27A-spiro-adamantyl amine complex predicts with accuracy the position of the ligands and waters inside the pore in the X-ray crystal structure of the M2(22-46) V27A complex.

X-ray Crystal Structures of the Influenza M2 Proton Channel Drug-Resistant V27A Mutant Bound to a Spiro-Adamantyl Amine Inhibitor Reveal the Mechanism of Adamantane Resistance.,Thomaston JL, Konstantinidi A, Liu L, Lambrinidis G, Tan J, Caffrey M, Wang J, Degrado WF, Kolocouris A Biochemistry. 2020 Feb 4;59(4):627-634. doi: 10.1021/acs.biochem.9b00971. Epub, 2020 Jan 13. PMID:31894969<ref>PMID:31894969</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 6oug" style="background-color:#fffaf0;"></div>

==See Also==
*[[Ion channels 3D structures|Ion channels 3D structures]]
*[[M2 protein|M2 protein]]
== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: DeGrado WF]]
[[Category: Liu L]]
[[Category: Thomaston JL]]