View source for 7k93


==DENV2 NS1 in complex with neutralizing 2B7 single chain Fab variable region (scFv)==
<StructureSection load='7k93' size='340' side='right'caption='[[7k93]], [[Resolution|resolution]] 2.89&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7k93]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Dengue_virus_2 Dengue virus 2] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7K93 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7K93 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]] 2.89&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=7k93 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7k93 OCA], [https://pdbe.org/7k93 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7k93 RCSB], [https://www.ebi.ac.uk/pdbsum/7k93 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7k93 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/POLG_DEN26 POLG_DEN26] prM acts as a chaperone for envelope protein E during intracellular virion assembly by masking and inactivating envelope protein E fusion peptide. prM is matured in the last step of virion assembly, presumably to avoid catastrophic activation of the viral fusion peptide induced by the acidic pH of the trans-Golgi network. After cleavage by host furin, the pr peptide is released in the extracellular medium and small envelope protein M and envelope protein E homodimers are dissociated (By similarity).<ref>PMID:15956546</ref> <ref>PMID:16544248</ref> <ref>PMID:15944325</ref> <ref>PMID:19850911</ref> <ref>PMID:19754307</ref> <ref>PMID:19272179</ref>   Envelope protein E binding to host cell surface receptor is followed by virus internalization through clathrin-mediated endocytosis. Envelope protein E is subsequently involved in membrane fusion between virion and host late endosomes. Synthesized as a homodimer with prM which acts as a chaperone for envelope protein E. After cleavage of prM, envelope protein E dissociate from small envelope protein M and homodimerizes (By similarity).<ref>PMID:15956546</ref> <ref>PMID:16544248</ref> <ref>PMID:15944325</ref> <ref>PMID:19850911</ref> <ref>PMID:19754307</ref> <ref>PMID:19272179</ref>   Non-structural protein 1 is involved in virus replication and regulation of the innate immune response. Soluble and membrane-associated NS1 may activate human complement and induce host vascular leakage. This effect might explain the clinical manifestations of dengue hemorrhagic fever and dengue shock syndrome (By similarity).<ref>PMID:15956546</ref> <ref>PMID:16544248</ref> <ref>PMID:15944325</ref> <ref>PMID:19850911</ref> <ref>PMID:19754307</ref> <ref>PMID:19272179</ref>   Non-structural protein 2A may be involved viral RNA replication and capsid assembly (Potential).<ref>PMID:15956546</ref> <ref>PMID:16544248</ref> <ref>PMID:15944325</ref> <ref>PMID:19850911</ref> <ref>PMID:19754307</ref> <ref>PMID:19272179</ref>   Non-structural protein 2B is a required cofactor for the serine protease function of NS3 (By similarity).<ref>PMID:15956546</ref> <ref>PMID:16544248</ref> <ref>PMID:15944325</ref> <ref>PMID:19850911</ref> <ref>PMID:19754307</ref> <ref>PMID:19272179</ref>   Serine protease NS3 displays three enzymatic activities: serine protease, NTPase and RNA helicase. NS3 serine protease, in association with NS2B, performs its autocleavage and cleaves the polyprotein at dibasic sites in the cytoplasm: C-prM, NS2A-NS2B, NS2B-NS3, NS3-NS4A, NS4A-2K and NS4B-NS5. NS3 RNA helicase binds RNA and unwinds dsRNA in the 3' to 5' direction (By similarity).<ref>PMID:15956546</ref> <ref>PMID:16544248</ref> <ref>PMID:15944325</ref> <ref>PMID:19850911</ref> <ref>PMID:19754307</ref> <ref>PMID:19272179</ref>   Non-structural protein 4A induces host endoplasmic reticulum membrane rearrangements leading to the formation of virus-induced membranous vesicles hosting the dsRNA and polymerase, functioning as a replication complex. NS4A might also regulate the ATPase activity of the NS3 helicase (By similarity).<ref>PMID:15956546</ref> <ref>PMID:16544248</ref> <ref>PMID:15944325</ref> <ref>PMID:19850911</ref> <ref>PMID:19754307</ref> <ref>PMID:19272179</ref>   Peptide 2k functions as a signal peptide for NS4B and is required for the interferon antagonism activity of the latter (By similarity).<ref>PMID:15956546</ref> <ref>PMID:16544248</ref> <ref>PMID:15944325</ref> <ref>PMID:19850911</ref> <ref>PMID:19754307</ref> <ref>PMID:19272179</ref>   Non-structural protein 4B inhibits interferon (IFN)-induced host STAT1 phosphorylation and nuclear translocation, thereby preventing the establishment of cellular antiviral state by blocking the IFN-alpha/beta pathway.<ref>PMID:15956546</ref> <ref>PMID:16544248</ref> <ref>PMID:15944325</ref> <ref>PMID:19850911</ref> <ref>PMID:19754307</ref> <ref>PMID:19272179</ref>   RNA-directed RNA polymerase NS5 replicates the viral (+) and (-) genome, and performs the capping of genomes in the cytoplasm. NS5 methylates viral RNA cap at guanine N-7 and ribose 2'-O positions. Besides its role in genome replication, also prevents the establishment of cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) signaling pathway. Inhibits host TYK2 and STAT2 phosphorylation, thereby preventing activation of JAK-STAT signaling pathway (By similarity).<ref>PMID:15956546</ref> <ref>PMID:16544248</ref> <ref>PMID:15944325</ref> <ref>PMID:19850911</ref> <ref>PMID:19754307</ref> <ref>PMID:19272179</ref>   Capsid protein C self-assembles to form an icosahedral capsid about 30 nm in diameter. The capsid encapsulates the genomic RNA (By similarity).<ref>PMID:15956546</ref> <ref>PMID:16544248</ref> <ref>PMID:15944325</ref> <ref>PMID:19850911</ref> <ref>PMID:19754307</ref> <ref>PMID:19272179</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Medically important flaviviruses cause diverse disease pathologies and collectively are responsible for a major global disease burden. A contributing factor to pathogenesis is secreted flavivirus nonstructural protein 1 (NS1). Despite demonstrated protection by NS1-specific antibodies against lethal flavivirus challenge, the structural and mechanistic basis remains unknown. Here, we present three crystal structures of full-length dengue virus NS1 complexed with a flavivirus-cross-reactive, NS1-specific monoclonal antibody, 2B7, at resolutions between 2.89 and 3.96 angstroms. These structures reveal a protective mechanism by which two domains of NS1 are antagonized simultaneously. The NS1 wing domain mediates cell binding, whereas the beta-ladder triggers downstream events, both of which are required for dengue, Zika, and West Nile virus NS1-mediated endothelial dysfunction. These observations provide a mechanistic explanation for 2B7 protection against NS1-induced pathology and demonstrate the potential of one antibody to treat infections by multiple flaviviruses.

Structural basis for antibody inhibition of flavivirus NS1-triggered endothelial dysfunction.,Biering SB, Akey DL, Wong MP, Brown WC, Lo NTN, Puerta-Guardo H, Tramontini Gomes de Sousa F, Wang C, Konwerski JR, Espinosa DA, Bockhaus NJ, Glasner DR, Li J, Blanc SF, Juan EY, Elledge SJ, Mina MJ, Beatty PR, Smith JL, Harris E Science. 2021 Jan 8;371(6525):194-200. doi: 10.1126/science.abc0476. PMID:33414220<ref>PMID:33414220</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7k93" style="background-color:#fffaf0;"></div>

==See Also==
*[[Antibody 3D structures|Antibody 3D structures]]
*[[Monoclonal Antibodies 3D structures|Monoclonal Antibodies 3D structures]]
*[[Nonstructural protein 3D structures|Nonstructural protein 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Dengue virus 2]]
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Akey DL]]
[[Category: Smith JL]]