5o6v | pdb_00005o6v
The cryo-EM structure of Tick-borne encephalitis virus complexed with Fab fragment of neutralizing antibody 19/1786
Structural highlights
Function[POLG_TBEVH] Capsid protein C: 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.[UniProtKB:P17763] Capsid protein C: Inhibits RNA silencing by interfering with host Dicer.[UniProtKB:P03314] Peptide pr: Prevents premature fusion activity of envelope proteins in trans-Golgi by binding to envelope protein E at pH6.0. After virion release in extracellular space, gets dissociated from E dimers.[UniProtKB:P17763] Protein prM: 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] Small envelope protein M: 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] Envelope protein E: Binds to host cell surface receptor and mediates fusion between viral and cellular membranes. 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] Non-structural protein 1: 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] Non-structural protein 2A: Component of the viral RNA replication complex that functions in virion assembly and antagonizes the host immune response.[UniProtKB:P17763] Non-structural protein 2B: Required cofactor for the serine protease function of NS3 (By similarity). May have membrane-destabilizing activity and form viroporins (By similarity).[UniProtKB:P17763][PROSITE-ProRule:PRU00859] 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.[PROSITE-ProRule:PRU00860] Non-structural protein 4A: Regulates the ATPase activity of the NS3 helicase activity. NS4A allows NS3 helicase to conserve energy during unwinding.[UniProtKB:Q9Q6P4] Peptide 2k: Functions as a signal peptide for NS4B and is required for the interferon antagonism activity of the latter.[UniProtKB:P17763] Non-structural protein 4B: Induces the formation of ER-derived membrane vesicles where the viral replication takes place. 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. Inhibits STAT2 translocation in the nucleus after IFN-alpha treatment.[UniProtKB:Q9Q6P4] RNA-directed RNA polymerase NS5: Replicates the viral (+) and (-) 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 genome replication, also prevents the establishment of cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) signaling pathway (PubMed:18042258). Inhibits host TYK2 and STAT2 phosphorylation, thereby preventing activation of JAK-STAT signaling pathway (PubMed:18042258).[UniProtKB:P17763][1] Publication Abstract from PubMedTick-borne encephalitis virus (TBEV) causes 13,000 cases of human meningitis and encephalitis annually. However, the structure of the TBEV virion and its interactions with antibodies are unknown. Here, we present cryo-EM structures of the native TBEV virion and its complex with Fab fragments of neutralizing antibody 19/1786. Flavivirus genome delivery depends on membrane fusion that is triggered at low pH. The virion structure indicates that the repulsive interactions of histidine side chains, which become protonated at low pH, may contribute to the disruption of heterotetramers of the TBEV envelope and membrane proteins and induce detachment of the envelope protein ectodomains from the virus membrane. The Fab fragments bind to 120 out of the 180 envelope glycoproteins of the TBEV virion. Unlike most of the previously studied flavivirus-neutralizing antibodies, the Fab fragments do not lock the E-proteins in the native-like arrangement, but interfere with the process of virus-induced membrane fusion. Structure of tick-borne encephalitis virus and its neutralization by a monoclonal antibody.,Fuzik T, Formanova P, Ruzek D, Yoshii K, Niedrig M, Plevka P Nat Commun. 2018 Jan 30;9(1):436. doi: 10.1038/s41467-018-02882-0. PMID:29382836[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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