Next Article in Journal
Influence of Different Drying Techniques on Phenolic Compounds, Antioxidant Capacity and Colour of Ziziphus jujube Mill. Fruits
Next Article in Special Issue
New HSV-1 Anti-Viral 1′-Homocarbocyclic Nucleoside Analogs with an Optically Active Substituted Bicyclo[2.2.1]Heptane Fragment as a Glycoside Moiety
Previous Article in Journal
Anthocyanin Profile of Elderberry Juice: A Natural-Based Bioactive Colouring Ingredient with Potential Food Application
Previous Article in Special Issue
An Expeditious Total Synthesis of 5′-Deoxy-toyocamycin and 5′-Deoxysangivamycin
Open AccessArticle

(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

1
Instituto de Química Médica (IQM-CSIC), Juan de la Cierva 3, E-28006 Madrid, Spain
2
Institut de Biologia Molecular de Barcelona (IBMB-CSIC), Parc Científic de Barcelona, Josep Samitier 1–5, 08028 Barcelona, Spain
3
Area de Farmacología, Departamento de Ciencias Biomédicas, Unidad Asociada al IQM-CSIC, Universidad de Alcalá, E-28805 Alcalá de Henares, Madrid, Spain
*
Authors to whom correspondence should be addressed.
Academic Editors: Katherine L. Seley-Radtke and Theodore K. Dayie
Molecules 2019, 24(13), 2360; https://doi.org/10.3390/molecules24132360
Received: 30 May 2019 / Revised: 21 June 2019 / Accepted: 24 June 2019 / Published: 26 June 2019
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. View Full-Text
Keywords: foot-and-mouth disease virus; RNA-dependent RNA polymerase; 5-fluorouracil; uridylylation inhibition; VPg foot-and-mouth disease virus; RNA-dependent RNA polymerase; 5-fluorouracil; uridylylation inhibition; VPg
Show Figures

Graphical abstract

MDPI and ACS Style

de Castro, S.; Ferrer-Orta, C.; Mills, A.; Fernández-Cureses, G.; Gago, F.; Verdaguer, N.; Camarasa, M.-J. (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, 24, 2360.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop