View source for 5ywo


==Structure of JEV-2F2 Fab complex==
<SX load='5ywo' size='340' side='right' viewer='molstar' caption='[[5ywo]], [[Resolution|resolution]] 4.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5ywo]] is a 10 chain structure with sequence from [https://en.wikipedia.org/wiki/Japanese_encephalitis_virus Japanese encephalitis virus] 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=5YWO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5YWO FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 4.7&#8491;</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=5ywo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ywo OCA], [https://pdbe.org/5ywo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ywo RCSB], [https://www.ebi.ac.uk/pdbsum/5ywo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ywo ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/POLG_JAEVJ POLG_JAEVJ] Plays a role in virus budding by binding to the cell membrane and gathering the viral RNA into a nucleocapsid that forms the core of a mature virus particle. During virus entry, may induce genome penetration into the host cytoplasm after hemifusion induced by the surface proteins. Can migrate to the cell nucleus where it modulates host functions. Overcomes the anti-viral effects of host EXOC1 by sequestering and degrading the latter through the proteasome degradation pathway.[UniProtKB:P17763]  Inhibits RNA silencing by interfering with host Dicer.[UniProtKB:P03314]  Prevents premature fusion activity of envelope proteins in trans-Golgi by binding to envelope protein E at pH 6.0. After virion release in extracellular space, gets dissociated from E dimers.[UniProtKB:P17763]  Acts as a chaperone for envelope protein E during intracellular virion assembly by masking and inactivating envelope protein E fusion peptide. prM is the only viral peptide matured by host furin in the trans-Golgi network probably to avoid catastrophic activation of the viral fusion activity in acidic Golgi compartment prior to virion release. prM-E cleavage is inefficient, and many virions are only partially matured. These uncleaved prM would play a role in immune evasion.[UniProtKB:P17763]  May play a role in virus budding. Exerts cytotoxic effects by activating a mitochondrial apoptotic pathway through M ectodomain. May display a viroporin activity.[UniProtKB:P17763]  Binds to host cell surface receptor and mediates fusion between viral and cellular membranes. Efficient virus attachment to cell is, at least in part, mediated by host HSPA5. Envelope protein is synthesized in the endoplasmic reticulum in the form of heterodimer with protein prM. They play a role in virion budding in the ER, and the newly formed immature particle is covered with 60 spikes composed of heterodimer between precursor prM and envelope protein E. The virion is transported to the Golgi apparatus where the low pH causes dissociation of PrM-E heterodimers and formation of E homodimers. prM-E cleavage is inefficient, and many virions are only partially matured. These uncleaved prM would play a role in immune evasion.[UniProtKB:P17763]  Involved in immune evasion, pathogenesis and viral replication. Once cleaved off the polyprotein, is targeted to three destinations: the viral replication cycle, the plasma membrane and the extracellular compartment. Essential for viral replication. Required for formation of the replication complex and recruitment of other non-structural proteins to the ER-derived membrane structures. Excreted as a hexameric lipoparticle that plays a role against host immune response. Antagonizing the complement function. Binds to the host macrophages and dendritic cells. Inhibits signal transduction originating from Toll-like receptor 3 (TLR3).[UniProtKB:Q9Q6P4]  Component of the viral RNA replication complex that functions in virion assembly and antagonizes the host alpha/beta interferon antiviral response.[UniProtKB:P14335]  Required cofactor for the serine protease function of NS3 (By similarity). May have membrane-destabilizing activity and form viroporins (By similarity).[UniProtKB:P27395][PROSITE-ProRule:PRU00859]  Displays three enzymatic activities: serine protease, NTPase and RNA helicase (By similarity). 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 (By similarity). NS3 RNA helicase binds RNA and unwinds dsRNA in the 3' to 5' direction.[UniProtKB:P27395][PROSITE-ProRule:PRU00860]  Regulates the ATPase activity of the NS3 helicase activity. NS4A allows NS3 helicase to conserve energy during unwinding.[UniProtKB:Q9Q6P4]  Functions as a signal peptide for NS4B and is required for the interferon antagonism activity of the latter.[UniProtKB:P17763]  Induces the formation of ER-derived membrane vesicles where the viral replication takes place (By similarity). 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 (By similarity). Inhibits STAT2 translocation in the nucleus after IFN-alpha treatment (By similarity).[UniProtKB:Q9Q6P4]  Replicates the viral (+) and (-) RNA genome, and performs the capping of genomes in the cytoplasm (By similarity). NS5 methylates viral RNA cap at guanine N-7 and ribose 2'-O positions (By similarity). Besides its role in RNA genome replication, also prevents the establishment of cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) signaling pathway (By similarity). Inhibits host TYK2 and STAT2 phosphorylation, thereby preventing activation of JAK-STAT signaling pathway (By similarity).[UniProtKB:P27395][UniProtKB:Q9Q6P4]
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== Publication Abstract from PubMed ==
Japanese encephalitis virus (JEV), closely related to dengue, Zika, yellow fever and West Nile viruses, remains neglected and not well characterized (1) . JEV is the leading causative agent of encephalitis, and is responsible for thousands of deaths each year in Asia. Humoral immunity is essential for protecting against flavivirus infections and passive immunization has been demonstrated to be effective in curing disease(2,3). Here, we demonstrate that JEV-specific monoclonal antibodies, 2F2 and 2H4, block attachment of the virus to its receptor and also prevent fusion of the virus. Neutralization of JEV by these antibodies is exceptionally potent and confers clear therapeutic benefit in mouse models. A single 20 mug dose of these antibodies resulted in 100% survival and complete clearance of JEV from the brains of mice. The 4.7 A and 4.6 A resolution cryo-electron microscopy structures of JEV-2F2-Fab and JEV-2H4-Fab complexes, together with the crystal structure of 2H4 Fab and our recent near-atomic structure of JEV (4) , unveil the nature and location of epitopes targeted by the antibodies. Both 2F2 and 2H4 Fabs bind quaternary epitopes that span across three adjacent envelope proteins. Our results provide a structural and molecular basis for the application of 2F2 and 2H4 to treat JEV infection.

Structural basis for neutralization of Japanese encephalitis virus by two potent therapeutic antibodies.,Qiu X, Lei Y, Yang P, Gao Q, Wang N, Cao L, Yuan S, Huang X, Deng Y, Ma W, Ding T, Zhang F, Wu X, Hu J, Liu SL, Qin C, Wang X, Xu Z, Rao Z Nat Microbiol. 2018 Mar;3(3):287-294. doi: 10.1038/s41564-017-0099-x. Epub 2018, Jan 29. PMID:29379207<ref>PMID:29379207</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 5ywo" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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[[Category: Japanese encephalitis virus]]
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Cao L]]
[[Category: Gao Q]]
[[Category: Lei YF]]
[[Category: Qiu X]]
[[Category: Rao Z]]
[[Category: Wang N]]
[[Category: Wang X]]
[[Category: Xu ZK]]
[[Category: Yang P]]
[[Category: Yuan S]]