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Structure-based energetics of protein interfaces guides foot-and-mouth disease virus vaccine design

DOI: 10.1038/nsmb.3096 DOI Help
PMID: 26389739 PMID Help

Authors: Abhay Kotecha (University of Oxford) , Julian Seago (Pirbright Institute) , Katherine Scott (Agricultural Research Council-Onderstepoort Veterinary Institute) , Alison Burman (Pirbright Institute) , Silvia Loureiro (University of Reading) , Jingshan Ren (University of Oxford) , Claudine Porta (Pirbright Institute) , Helen M Ginn (University of Oxford) , Terry Jackson (Pirbright Institute) , Eva Perez-martin (Pirbright Institute) , C Alistair Siebert (University of Oxford) , Guntram Paul (Merck Sharp & Dohme Animal Health) , Juha T Huiskonen (University of Oxford) , Ian M Jones (University of Reading) , Robert Esnouf (University of Oxford) , Elizabeth Fry (University of Oxford) , Francois F Maree (Agricultural Research Council-Onderstepoort Veterinary Institute) , Bryan Charleston (Pirbright Institute) , Dave Stuart (Diamond Light Source)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Structural & Molecular Biology

State: Published (Approved)
Published: September 2015
Diamond Proposal Number(s): 10627

Open Access Open Access

Abstract: Virus capsids are primed for disassembly, yet capsid integrity is key to generating a protective immune response. Foot-and-mouth disease virus (FMDV) capsids comprise identical pentameric protein subunits held together by tenuous noncovalent interactions and are often unstable. Chemically inactivated or recombinant empty capsids, which could form the basis of future vaccines, are even less stable than live virus. Here we devised a computational method to assess the relative stability of protein-protein interfaces and used it to design improved candidate vaccines for two poorly stable, but globally important, serotypes of FMDV: O and SAT2. We used a restrained molecular dynamics strategy to rank mutations predicted to strengthen the pentamer interfaces and applied the results to produce stabilized capsids. Structural analyses and stability assays confirmed the predictions, and vaccinated animals generated improved neutralizing-antibody responses to stabilized particles compared to parental viruses and wild-type capsids.

Subject Areas: Biology and Bio-materials


Instruments: I24-Microfocus Macromolecular Crystallography