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==Complex of poliovirus with VHH PVSP6A== | ==Complex of poliovirus with VHH PVSP6A== | ||
<StructureSection load='3jbd' size='340' side='right' caption='[[3jbd]], [[Resolution|resolution]] 4.70Å' scene=''> | <StructureSection load='3jbd' size='340' side='right' caption='[[3jbd]], [[Resolution|resolution]] 4.70Å' scene=''> | ||
Revision as of 16:46, 10 May 2016
Complex of poliovirus with VHH PVSP6A
Structural highlights
Function[POLG_POL1M] 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.[1] [2] [3] VP0 precursor is a component of immature procapsids (By similarity).[4] [5] [6] 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.[7] [8] [9] Protein 2B affects membrane integrity and cause an increase in membrane permeability (By similarity).[10] [11] [12] Protein 2C associates with and induces structural rearrangements of intracellular membranes. It displays RNA-binding, nucleotide binding and NTPase activities.[13] [14] [15] Protein 3A, via its hydrophobic domain, serves as membrane anchor. It also inhibits endoplasmic reticulum-to-Golgi transport (By similarity).[16] [17] [18] 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).[19] [20] [21] RNA-directed RNA polymerase 3D-POL replicates genomic and antigenomic RNA by recognizing replications specific signals (By similarity).[22] [23] [24] Publication Abstract from PubMedNanobodies(R), or VHHs, that recognize poliovirus type 1 have previously been selected and characterized as candidates for antiviral agents or reagents for standardization of vaccine quality control. In this study, we present high-resolution cryo-electron microscopy reconstructions of poliovirus with five neutralizing VHHs. All VHHs bind the capsid in the canyon at sites that extensively overlap the poliovirus receptor binding site. In contrast, the interaction involves a unique (and surprisingly extensive) surface for each of the five VHHs. Five regions of the capsid were found to participate in binding with all five the VHHs. Four of these five regions are known to alter during the expansion of the capsid associated with viral entry. Interestingly, binding of one of the VHHs, PVSS21E, resulted in significant changes of the capsid structure and thus seems to trap the virus in an early stage of expansion. IMPORTANCE: We describe the cryo-EM structures of complexes of five neutralizing VHHs with the Mahoney strain of type 1 poliovirus at resolutions ranging from 3.8-6.3A. All five VHHs bind deep in the virus canyon at similar sites that overlap extensively with the binding site for the receptor (CD155). The binding surfaces on the VHHs are surprisingly extensive, but despite the similarity of the binding surface on the virus, the binding surface on the VHHs is unique for each VHH. In four of the five complexes the virus remains essentially unchanged, but for the fifth there are significant changes reminiscent of, but smaller in magnitude than, changes associated with cell entry, suggesting that this VHH has trapped the virus in a previously undescribed early intermediate state. The neutralizing mechanisms of the VHHs and their potential use as quality control agents for the end game of poliovirus eradication are discussed. Five of five VHHs neutralizing poliovirus bind the receptor-binding site.,Strauss M, Schotte L, Thys B, Filman DJ, Hogle JM J Virol. 2016 Jan 13. pii: JVI.03017-15. PMID:26764003[25] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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