1piv
BINDING OF THE ANTIVIRAL DRUG WIN51711 TO THE SABIN STRAIN OF TYPE 3 POLIOVIRUS: STRUCTURAL COMPARISON WITH DRUG BINDING IN RHINOVIRUS 14
Structural highlights
FunctionPOLG_POL3L Capsid proteins VP1, VP2, VP3 and VP4 form a closed capsid enclosing the viral positive strand RNA genome. VP4 lies on the inner surface of the protein shell formed by VP1, VP2 and VP3. All the three latter proteins contain a beta-sheet structure called beta-barrel jelly roll. Together they form an icosahedral capsid (T=3) composed of 60 copies of each VP1, VP2, and VP3, with a diameter of approximately 300 Angstroms. VP1 is situated at the 12 fivefold axes, whereas VP2 and VP3 are located at the quasi-sixfold axes. The interaction of five VP1 proteins in the fivefold axes results in a prominent protusion extending to about 25 Angstroms from the capsid shell. The resulting structure appears as a steep plateau encircled by a valley or cleft. This depression also termed canyon is the receptor binding site. The capsid interacts with human PVR at this site to provide virion attachment to target cell. This attachment induces virion internalization predominantly through clathrin- and caveolin-independent endocytosis in Hela cells and through caveolin-mediated endocytosis in brain microvascular endothelial cells. VP4 and VP1 subsequently undergo conformational changes leading to the formation of a pore in the endosomal membrane, thereby delivering the viral genome into the cytoplasm (By similarity). VP0 precursor is a component of immature procapsids (By similarity). Protein 2A is a cysteine protease that is responsible for the cleavage between the P1 and P2 regions. It cleaves the host translation initiation factor EIF4G1, in order to shut down the capped cellular mRNA transcription (By similarity). Protein 2B affects membrane integrity and cause an increase in membrane permeability (By similarity). Protein 2C associates with and induces structural rearrangements of intracellular membranes. It displays RNA-binding, nucleotide binding and NTPase activities (By similarity). Protein 3A, via its hydrophobic domain, serves as membrane anchor. It also inhibits endoplasmic reticulum-to-Golgi transport (By similarity). Protein 3C is a cysteine protease that generates mature viral proteins from the precursor polyprotein. In addition to its proteolytic activity, it binds to viral RNA, and thus influences viral genome replication. RNA and substrate bind co-operatively to the protease (By similarity). RNA-directed RNA polymerase 3D-POL replicates genomic and antigenomic RNA by recognizing replications specific signals (By similarity). Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe crystal structure of the Sabin strain of type 3 poliovirus (P3/Sabin) complexed with the antiviral drug WIN51711 has been determined at 2.9 A resolution. Drugs of this kind are known to inhibit the uncoating of the virus during infection, by stabilizing the capsid against receptor-induced conformational changes. The electron density for the bound drug is very well defined so that its position and orientation are unambiguous. The drug binds in a nearly extended conformation, slightly bent in the middle, in a blind pocket formed predominantly by hydrophobic residues in the core of the beta-barrel of capsid protein VP1. Comparisons between this structure, the corresponding drug complex in human rhinovirus 14 (HRV 14), and the native structures of both viruses demonstrate that the binding of WIN51711 has markedly different effects on the structures of these two viruses. Unlike HRV14, wherein large conformational changes are observed in the coat protein after drug binding, the binding of this drug in poliovirus does not induce any significant conformational changes in the structure of the capsid protein, though the drug has a greater inhibitory effect in P3/Sabin than in HRV14. The implications of this result for the mechanism of capsid stabilization are discussed. Binding of the antiviral drug WIN51711 to the sabin strain of type 3 poliovirus: structural comparison with drug binding in rhinovirus 14.,Hiremath CN, Grant RA, Filman DJ, Hogle JM Acta Crystallogr D Biol Crystallogr. 1995 Jul 1;51(Pt 4):473-89. PMID:15299834[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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