5bnp
From Proteopedia
Crystal structure of human enterovirus D68 in complex with 3'SLN
Structural highlights
FunctionPOLG_HED68 Component of immature procapsids, which is cleaved into capsid proteins VP4 and VP2 after maturation (By similarity). Allows the capsid to remain inactive before the maturation step (By similarity).[UniProtKB:P03300] Forms an icosahedral capsid of pseudo T=3 symmetry with capsid proteins VP2 and VP3 (By similarity). The capsid is 300 Angstroms in diameter, composed of 60 copies of each capsid protein and enclosing the viral positive strand RNA genome (By similarity). Capsid protein VP1 mainly forms the vertices of the capsid (By similarity). Capsid protein VP1, together with VP3, interacts with host cell sialic acids to provide virion attachment to target host cells (PubMed:26563423). This attachment induces virion internalization (PubMed:26563423). After binding to its receptor, the capsid undergoes conformational changes (By similarity). Capsid protein VP1 N-terminus (that contains an amphipathic alpha-helix) and capsid protein VP4 are externalized (By similarity). Together, they shape a pore in the host membrane through which viral genome is translocated to host cell cytoplasm (By similarity).[UniProtKB:P03300][1] Forms an icosahedral capsid of pseudo T=3 symmetry with capsid proteins VP2 and VP3 (By similarity). The capsid is 300 Angstroms in diameter, composed of 60 copies of each capsid protein and enclosing the viral positive strand RNA genome (By similarity).[UniProtKB:P03300] Forms an icosahedral capsid of pseudo T=3 symmetry with capsid proteins VP2 and VP3 (By similarity). The capsid is 300 Angstroms in diameter, composed of 60 copies of each capsid protein and enclosing the viral positive strand RNA genome (By similarity). Capsid protein VP3, together with VP1, interacts with host cell sialic acids to provide virion attachment to target host cells (PubMed:26563423).[UniProtKB:P03300][2] Lies on the inner surface of the capsid shell (By similarity). After binding to the host receptor, the capsid undergoes conformational changes (By similarity). Capsid protein VP4 is released, Capsid protein VP1 N-terminus is externalized, and together, they shape a pore in the host membrane through which the viral genome is translocated into the host cell cytoplasm (By similarity).[UniProtKB:P03300] Cysteine protease that cleaves viral polyprotein and specific host proteins (By similarity). It is responsible for the autocatalytic cleavage between the P1 and P2 regions, which is the first cleavage occurring in the polyprotein (By similarity). Cleaves also the host translation initiation factor EIF4G1, in order to shut down the capped cellular mRNA translation (By similarity). Inhibits the host nucleus-cytoplasm protein and RNA trafficking by cleaving host members of the nuclear pores (By similarity). Counteracts stress granule formation probably by antagonizing its assembly or promoting its dissassembly (PubMed:30867299). Also plays a role in the suppression of host innate immunity through cleavage of host TRAF3, a component of the signaling cascade required to produce type I interferons (PubMed:33148796).[UniProtKB:P03300][3] [4] Plays an essential role in the virus replication cycle by acting as a viroporin. Creates a pore in the host reticulum endoplasmic and as a consequence releases Ca2+ in the cytoplasm of infected cell. In turn, high levels of cytoplasmic calcium may trigger membrane trafficking and transport of viral ER-associated proteins to viroplasms, sites of viral genome replication.[UniProtKB:P03300] Induces and associates with structural rearrangements of intracellular membranes. Displays RNA-binding, nucleotide binding and NTPase activities. May play a role in virion morphogenesis and viral RNA encapsidation by interacting with the capsid protein VP3.[UniProtKB:P03300] Localizes the viral replication complex to the surface of membranous vesicles. Together with protein 3CD binds the Cis-Active RNA Element (CRE) which is involved in RNA synthesis initiation. Acts as a cofactor to stimulate the activity of 3D polymerase, maybe through a nucleid acid chaperone activity.[UniProtKB:P03300] Localizes the viral replication complex to the surface of membranous vesicles (By similarity). It inhibits host cell endoplasmic reticulum-to-Golgi apparatus transport and causes the disassembly of the Golgi complex, possibly through GBF1 interaction (By similarity). This would result in depletion of MHC, trail receptors and IFN receptors at the host cell surface (By similarity). Plays an essential role in viral RNA replication by recruiting ACBD3 and PI4KB at the viral replication sites, thereby allowing the formation of the rearranged membranous structures where viral replication takes place (PubMed:31381608).[UniProtKB:P03300][5] Acts as a primer for viral RNA replication and remains covalently bound to viral genomic RNA. VPg is uridylylated prior to priming replication into VPg-pUpU (By similarity). The oriI viral genomic sequence may act as a template for this. The VPg-pUpU is then used as primer on the genomic RNA poly(A) by the RNA-dependent RNA polymerase to replicate the viral genome (By similarity). Following genome release from the infecting virion in the cytoplasm, the VPg-RNA linkage is probably removed by host TDP2 (By similarity). During the late stage of the replication cycle, host TDP2 is excluded from sites of viral RNA synthesis and encapsidation, allowing for the generation of progeny virions (By similarity).[UniProtKB:P03300] Involved in the viral replication complex and viral polypeptide maturation. It exhibits protease activity with a specificity and catalytic efficiency that is different from protease 3C. Protein 3CD lacks polymerase activity. Protein 3CD binds to the 5'UTR of the viral genome.[UniProtKB:P03300] Major viral protease that mediates proteolytic processing of the polyprotein (By similarity). Cleaves host EIF5B, contributing to host translation shutoff (By similarity). Cleaves also host PABPC1, contributing to host translation shutoff (By similarity). Binds and inhibits host IFIH1/MDA5, thereby inhibiting the type-I IFN production and the establishment of the antiviral state (PubMed:28424289). Cleaves host MAP3K7/TAK1, resulting in inhibition of TRAF6-triggered NF-kappa-B induction (PubMed:28424289). Cleaves host TICAM1; this interaction allows the virus to disrupt host TLR3 signaling (PubMed:24672048). Cleaves host IRF7, resulting in inhibition of type-I IFN production (PubMed:26608321). Cleaves host NLRP1, triggers host N-glycine-mediated degradation of the autoinhibitory NLRP1 N-terminal fragment (PubMed:33410748).[UniProtKB:P03300][UniProtKB:P03303][6] [7] [8] [9] Replicates the viral genomic RNA on the surface of intracellular membranes. May form linear arrays of subunits that propagate along a strong head-to-tail interaction called interface-I. Covalently attaches UMP to a tyrosine of VPg, which is used to prime RNA synthesis. The positive stranded RNA genome is first replicated at virus induced membranous vesicles, creating a dsRNA genomic replication form. This dsRNA is then used as template to synthesize positive stranded RNA genomes. ss(+)RNA genomes are either translated, replicated or encapsidated.[UniProtKB:P03300] Publication Abstract from PubMedHuman enterovirus D68 (EV-D68) is a causative agent of childhood respiratory diseases and has now emerged as a global public health threat. Nevertheless, knowledge of the tissue tropism and pathogenesis of EV-D68 has been hindered by a lack of studies on the receptor-mediated EV-D68 entry into host cells. Here we demonstrate that cell surface sialic acid is essential for EV-D68 to bind to and infect susceptible cells. Crystal structures of EV-D68 in complex with sialylated glycan receptor analogues show that they bind into the 'canyon' on the virus surface. The sialic acid receptor induces a cascade of conformational changes in the virus to eject a fatty-acid-like molecule that regulates the stability of the virus. Thus, virus binding to a sialic acid receptor and to immunoglobulin-like receptors used by most other enteroviruses share a conserved mechanism for priming viral uncoating and facilitating cell entry. Sialic acid-dependent cell entry of human enterovirus D68.,Liu Y, Sheng J, Baggen J, Meng G, Xiao C, Thibaut HJ, van Kuppeveld FJ, Rossmann MG Nat Commun. 2015 Nov 13;6:8865. doi: 10.1038/ncomms9865. PMID:26563423[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Enterovirus D68 | Large Structures | Liu Y | Meng G | Rossmann MG | Sheng J | Xiao C
