scholarly journals Structures of EV71 RNA-dependent RNA polymerase in complex with substrate and analogue provide a drug target against the hand-foot-and-mouth disease pandemic in China

2010 ◽  
Vol 1 (5) ◽  
pp. 491-500 ◽  
Author(s):  
Yang Wu ◽  
Zhiyong Lou ◽  
Yi Miao ◽  
Yue Yu ◽  
Hui Dong ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Drug Target ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Rna Dependent Rna Polymerase ◽  
Foot And Mouth

scholarly journals Structure of Foot-and-Mouth Disease Virus RNA-dependent RNA Polymerase and Its Complex with a Template-Primer RNA

2004 ◽  
Vol 279 (45) ◽  
pp. 47212-47221 ◽  
Author(s):  
Cristina Ferrer-Orta ◽  
Armando Arias ◽  
Rosa Perez-Luque ◽  
Cristina Escarmís ◽  
Esteban Domingo ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Disease Virus ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Rna Dependent Rna Polymerase ◽  
Virus Rna ◽  
Mouth Disease Virus ◽  
Foot And Mouth ◽  
Primer Rna

scholarly journals (F)uridylylated Peptides Linked to VPg1 of Foot-and- Mouth Disease Virus (FMDV): Design, Synthesis and X-Ray Crystallography of the Complexes with FMDV RNA-Dependent RNA Polymerase

Molecules ◽  
2019 ◽  
Vol 24 (13) ◽  
pp. 2360 ◽  
Author(s):  
Sonia de Castro ◽  
Cristina Ferrer-Orta ◽  
Alberto Mills ◽  
Gloria Fernández-Cureses ◽  
Federico Gago ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Disease Virus ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Viral Rna ◽  
Hydroxyl Group ◽  
Rna Dependent Rna Polymerase ◽  
X Ray ◽  
Mouth Disease Virus ◽  
Foot And Mouth

Foot-and-mouth disease virus (FMDV) is an RNA virus belonging to the Picornaviridae family that contains three small viral proteins (VPgs), named VPg1, VPg2 and VPg3, linked to the 5′-end of the viral genome. These VPg proteins act as primers for RNA replication, which is initiated by the consecutive binding of two UMP molecules to the hydroxyl group of Tyr3 in VPg. This process, termed uridylylation, is catalyzed by the viral RNA-dependent RNA polymerase named 3Dpol. 5-Fluorouridine triphosphate (FUTP) is a potent competitive inhibitor of VPg uridylylation. Peptide analysis showed FUMP covalently linked to the Tyr3 of VPg. This fluorouridylylation prevents further incorporation of the second UMP residue. The molecular basis of how the incorporated FUMP blocks the incorporation of the second UMP is still unknown. To investigate the mechanism of inhibition of VPg uridylylation by FUMP, we have prepared a simplified 15-mer model of VPg1 containing FUMP and studied its x-ray crystal structure in complex with 3Dpol. Unfortunately, the fluorouridylylated VPg1 was disordered and not visible in the electron density maps; however, the structure of 3Dpol in the presence of VPg1-FUMP showed an 8 Å movement of the β9-α11 loop of the polymerase towards the active site cavity relative to the complex of 3Dpol with VPg1-UMP. The conformational rearrangement of this loop preceding the 3Dpol B motif seems to block the access of the template nucleotide to the catalytic cavity. This result may be useful in the design of new antivirals against not only FMDV but also other picornaviruses, since all members of this family require the uridylylation of their VPg proteins to initiate the viral RNA synthesis.

scholarly journals Selection and characterization of RNA aptamers to the RNA-dependent RNA polymerase from foot-and-mouth disease virus

RNA ◽  
2006 ◽  
Vol 12 (11) ◽  
pp. 1970-1979 ◽  
Author(s):  
M. Ellingham ◽  
D. H.J. Bunka ◽  
D. J. Rowlands ◽  
N. J. Stonehouse
Keyword(s):  
Rna Polymerase ◽  
Disease Virus ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Rna Aptamers ◽  
Rna Dependent Rna Polymerase ◽  
Mouth Disease Virus ◽  
Foot And Mouth

scholarly journals Inhibitors of Foot and Mouth Disease Virus Targeting a Novel Pocket of the RNA-Dependent RNA Polymerase

PLoS ONE ◽  
2010 ◽  
Vol 5 (12) ◽  
pp. e15049 ◽  
Author(s):  
Ryan C. Durk ◽  
Kamalendra Singh ◽  
Ceili A. Cornelison ◽  
Devendra K. Rai ◽  
Kayla B. Matzek ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Disease Virus ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Rna Dependent Rna Polymerase ◽  
Mouth Disease Virus ◽  
Foot And Mouth

scholarly journals Higher-order structures of the foot-and-mouth disease virus RNA-dependent RNA polymerase required for dynamic inter-molecular interactions involved in viral genome replication

2020 ◽  
Author(s):  
Eleni-Anna Loundras ◽  
James Streetley ◽  
Morgan R. Herod ◽  
Rebecca F. Thompson ◽  
Mark Harris ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Disease Virus ◽  
Molecular Interactions ◽  
Foot And Mouth Disease ◽  
Higher Order ◽  
Mouth Disease ◽  
Genome Replication ◽  
Rna Dependent Rna Polymerase ◽  
Mouth Disease Virus ◽  
Foot And Mouth

AbstractReplication of many positive-sense RNA viruses occurs within intracellular membrane-associated compartments. These are believed to provide a favourable environment for replication to occur, concentrating essential viral structural and non-structural components, as well as protecting these components from host-cell pathogen recognition and innate immune responses. However, the details of the molecular interactions and dynamics within these structures is very limited. One of the key components of the replication machinery is the RNA-dependent RNA polymerase, RdRp. This enzyme has been shown to form higher-order fibrils in vitro. Here, using the RdRp from foot-and-mouth disease virus (termed 3Dpol), we report fibril structures, solved at ~7-9 Å resolution by cryo-EM, revealing multiple conformations of a flexible assembly. Fitting high-resolution coordinates led to the definition of potential intermolecular interactions. We employed mutagenesis using a sub-genomic replicon system to probe the importance of these interactions for replication. We use these data to propose models for the role of higher order 3Dpol complexes as a dynamic scaffold within which RNA replication can occur.

scholarly journals Factors Required for the Uridylylation of the Foot-and-Mouth Disease Virus 3B1, 3B2, and 3B3 Peptides by the RNA-Dependent RNA Polymerase (3Dpol) In Vitro

2005 ◽  
Vol 79 (12) ◽  
pp. 7698-7706 ◽  
Author(s):  
Arabinda Nayak ◽  
Ian G. Goodfellow ◽  
Graham J. Belsham
Keyword(s):  
Rna Polymerase ◽  
Disease Virus ◽  
Rna Synthesis ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Coding Region ◽  
Mouth Disease Virus ◽  
Foot And Mouth ◽  
Positive Strand Rna

ABSTRACT The 5′ terminus of picornavirus genomic RNA is covalently linked to the virus-encoded peptide 3B (VPg). Foot-and-mouth disease virus (FMDV) is unique in encoding and using 3 distinct forms of this peptide. These peptides each act as primers for RNA synthesis by the virus-encoded RNA polymerase 3Dpol. To act as the primer for positive-strand RNA synthesis, the 3B peptides have to be uridylylated to form VPgpU(pU). For certain picornaviruses, it has been shown that this reaction is achieved by the 3Dpol in the presence of the 3CD precursor plus an internal RNA sequence termed a cis-acting replication element (cre). The FMDV cre has been identified previously to be within the 5′ untranslated region, whereas all other picornavirus cre structures are within the viral coding region. The requirements for the in vitro uridylylation of each of the FMDV 3B peptides has now been determined, and the role of the FMDV cre (also known as the 3B-uridylylation site, or bus) in this reaction has been analyzed. The poly(A) tail does not act as a significant template for FMDV 3B uridylylation.

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