6xw7: Difference between revisions

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 ==Crystal structure of murine norovirus P domain in complex with Nanobody NB-5829 and glycochenodeoxycholate (GCDCA)==
-<StructureSection load='6xw7' size='340' side='right'caption='[[6xw7]]' scene=''>
+<StructureSection load='6xw7' size='340' side='right'caption='[[6xw7]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6XW7 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6XW7 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6xw7]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Alpaca Alpaca] and [http://en.wikipedia.org/wiki/Murine_norovirus_1 Murine norovirus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6XW7 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6XW7 FirstGlance]. <br>
-</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6xw7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xw7 OCA], [http://pdbe.org/6xw7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6xw7 RCSB], [http://www.ebi.ac.uk/pdbsum/6xw7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6xw7 ProSAT]</span></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CHO:GLYCOCHENODEOXYCHOLIC+ACID'>CHO</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6xw7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xw7 OCA], [http://pdbe.org/6xw7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6xw7 RCSB], [http://www.ebi.ac.uk/pdbsum/6xw7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6xw7 ProSAT]</span></td></tr>
 </table>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Human norovirus frequently causes outbreaks of acute gastroenteritis. Although discovered more than five decades ago, antiviral development has, until recently, been hampered by the lack of a reliable human norovirus cell culture system. Nevertheless, a lot of pathogenesis studies were accomplished using murine norovirus (MNV), which can be grown routinely in cell culture. In this study, we analysed a sizeable library of Nanobodies that were raised against the murine norovirus virion with the main purpose of developing Nanobody-based inhibitors. We discovered two types of neutralizing Nanobodies and analysed the inhibition mechanisms using X-ray crystallography, cryo-EM, and cell culture techniques. The first type bound on the top region of the protruding (P) domain. Interestingly, the Nanobody binding region closely overlapped the MNV receptor-binding site and collectively shared numerous P domain-binding residues. In addition, we showed that these Nanobodies competed with the soluble receptor and this action blocked virion attachment to cultured cells. The second type bound at a dimeric interface on the lower side of the P dimer. We discovered that these Nanobodies disrupted a structural change in the capsid associated with binding co-factors (i.e., metal cations/bile acid). Indeed, we found that capsids underwent major conformational changes following addition of Mg(2+) or Ca(2+) Ultimately, these Nanobodies directly obstructed a structural modification reserved for a post-receptor attachment stage. Altogether, our new data show that Nanobody-based inhibition could occur by blocking functional and structural capsid properties.IMPORTANCE This research discovered and analysed two different types of MNV neutralizing Nanobodies. The top-binding Nanobodies sterically inhibited the receptor-binding site, whereas the dimeric-binding Nanobodies interfered with a structural modification associated with co-factor binding. Moreover, we found that the capsid contained a number of vulnerable regions that were essential for viral replication. In fact, the capsid appeared to be organized in a state of flux, which could be important for co-factor/receptor binding functions. Blocking these capsid-binding events with Nanobodies directly inhibited essential capsid functions. Moreover, a number of MNV-specific Nanobody binding epitopes were comparable to human norovirus-specific Nanobody inhibitors. Therefore, this additional structural and inhibition information could be further exploited in the development of human norovirus antivirals.
+Nanobody mediated neutralization reveals an Achilles heel for norovirus.,Koromyslova AD, Devant JM, Kilic T, Sabin CD, Malak V, Hansman GS J Virol. 2020 Apr 22. pii: JVI.00660-20. doi: 10.1128/JVI.00660-20. PMID:32321816<ref>PMID:32321816</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6xw7" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: Alpaca]]
 [[Category: Large Structures]]
-[[Category: Hansman G]]
+[[Category: Murine norovirus 1]]
-[[Category: Kilic T]]
+[[Category: Hansman, G]]
-[[Category: Sabin C]]
+[[Category: Kilic, T]]
+[[Category: Sabin, C]]
+[[Category: Mnv]]
+[[Category: Neutralizing nanobody]]
+[[Category: Norovirus]]
+[[Category: Vhh]]
+[[Category: Viral protein]]