1887

Abstract

The crystal structure of a 15 amino acid synthetic peptide, corresponding to the sequence of the major antigenic site A (G–H loop of VP1) from a multiple variant of foot-and-mouth disease virus (FMDV), has been determined at 2·3 Å resolution. The variant peptide includes four amino acid substitutions in the loop relative to the previously studied peptide representing FMDV C-S8c1 and corresponds to the loop of a natural FMDV isolate of subtype C. The peptide was complexed with the Fab fragment of the neutralizing monoclonal antibody 4C4. The peptide adopts a compact fold with a nearly cyclic conformation and a disposition of the receptor-recognition motif Arg–Gly–Asp that is closely related to the previously determined structure for the viral loop, as part of the virion, and for unsubstituted synthetic peptide antigen bound to neutralizing antibodies. New structural findings include the observation that well-defined solvent molecules appear to play a major role in stabilizing the conformation of the peptide and its interactions with the antibody. Structural results are supported by molecular-dynamic simulations. The multiply substituted peptide developed compensatory mechanisms to bind the antibody with a conformation very similar to that of its unsubstituted counterpart. One water molecule, which for steric reasons could not occupy the same position in the unsubstituted antigen, establishes hydrogen bonds with three peptide amino acids. The constancy of the structure of an antigenic domain despite multiple amino acid substitutions has implications for vaccine design.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/0022-1317-81-6-1495
2000-06-01
2024-12-03
Loading full text...

Full text loading...

/deliver/fulltext/jgv/81/6/0811495a.html?itemId=/content/journal/jgv/10.1099/0022-1317-81-6-1495&mimeType=html&fmt=ahah

References

  1. Acharya, R., Fry, E., Stuart, D., Fox, G., Rowlands, D. & Brown, F. (1989). The three-dimensional structure of foot-and-mouth disease virus at 2·9 Å resolution.Nature 337, 709-716.[CrossRef] [Google Scholar]
  2. Bachrach, H. L. (1968). Foot and mouth disease virus.Annual Review of Microbiology 22, 201-244.[CrossRef] [Google Scholar]
  3. Beck, E. & Strohmaier, K. (1987). Subtyping of European foot-and-mouth disease virus strains by nucleotide sequence determination. Journal of Virology 61, 1621-1629. [Google Scholar]
  4. Berendsen, H. J. C., Postma, J. P. M., van Gunsteren, W. F., DiNola, A. & Haak, J. R. (1984). Molecular dynamics with coupling to an external bath.Journal of Chemical Physics 81, 3684-3690.[CrossRef] [Google Scholar]
  5. Berendsen, H. J., Van Gunsteren, W. F., Zwinderman, H. R. & Geurtsen, R. G. (1986). Simulations of proteins in water.Annals of the New York Academy of Sciences 482, 269-286.[CrossRef] [Google Scholar]
  6. Berinstein, A., Roivainen, M., Hovi, T., Mason, P. W. & Baxt, B. (1995). Antibodies to the vitronectin receptor (integrin alpha V beta 3) inhibit binding and infection of foot-and-mouth disease virus to cultured cells.Journal of Virology 69, 2664-2666. [Google Scholar]
  7. Bittle, J. L., Houghten, R. A., Alexander, H., Shinnick, T. M., Sutcliffe, J. G., Lerner, R. A., Rowlands, D. J. & Brown, F. (1982). Protection against foot-and-mouth disease by immunization with a chemically synthesized peptide predicted from the viral nucleotide sequence.Nature 298, 30-33.[CrossRef] [Google Scholar]
  8. Brown, F. (1994). Foot-and-mouth disease. In Synthetic Vaccines, pp. 416-432. Edited by B. H. Nicholson. Oxford: Blackwell Scientific.
  9. Brünger, A. T. (1992). XPLOR manual, version 3.0. Yale University, New Haven, CT, USA.
  10. Carreño, C., Roig, X., Cairo, J., Camarero, J., Mateu, M. G., Domingo, E., Giralt, E. & Andreu, D. (1992). Studies on antigenic variability of C strains of foot-and-mouth disease virus by means of synthetic peptides and monoclonal antibodies.International Journal of Peptide and Protein Research 39, 41-47. [Google Scholar]
  11. Clarke, B. E., Carroll, A. R., Rowlands, D. J., Nicholson, B. H., Houghten, R. A., Lerner, R. A. & Brown, F. (1983). Synthetic peptides mimic subtype specificity of foot-and-mouth disease virus.FEBS Letters 157, 261-264.[CrossRef] [Google Scholar]
  12. Curry, S., Fry, E., Blakemore, W., Abu-Ghazaleh, R., Jackson, T., King, A., Lea, S., Newman, J., Rowlands, D. & Stuart, D. (1996). Perturbations in the surface structure of A22 Iraq foot-and-mouth disease virus accompanying coupled changes in host cell specificity and antigenicity. Structure 4, 135-145.[CrossRef] [Google Scholar]
  13. Domingo, E. & Holland, J. J. (1992). Complications of RNA heterogeneity for the engineering of virus vaccines and antiviral agents. In Genetic Engineering, Principles and Methods, pp. 13-32. Edited by J. K. Setlow. New York: Plenum.
  14. Domingo, E., Mateu, M. G., Martı́nez, M. A., Dopazo, J., Moya, A. & Sobrino, F. (1990). Genetic variability and antigenic diversity of foot-and-mouth disease virus. In Applied Virology Research, pp. 233-266. Edited by E. Kurkstak, R. G. Marusyk, S. A. Murphy & M. H. V. Van Regenmortel. New York: Plenum.
  15. Domingo, E., Verdaguer, N., Ochoa, W. F., Ruiz-Jarabo, C. M., Sevilla, N., Baranowski, E., Mateu, M. G. & Fita, I. (1999). Biochemical and structural studies with neutralizing antibodies raised against foot-and-mouth disease virus. Virus Research 62, 169-175.[CrossRef] [Google Scholar]
  16. Fox, G., Parry, N. R., Barnett, P. V., McGinn, B., Rowlands, D. J. & Brown, F. (1989). The cell attachment site on foot-and-mouth disease virus includes the amino acid sequence RGD (arginine-glycine-aspartic acid). Journal of General Virology 70, 625-637.[CrossRef] [Google Scholar]
  17. Freire, E. (1999). The propagation of binding interactions to remote sites in proteins: analysis of the binding of the monoclonal antibody D1.3 to lysozyme. Proceedings of the National Academy of Sciences, USA 96, 10118-10122.[CrossRef] [Google Scholar]
  18. Hernández, J., Valero, M. L., Andreu, D., Domingo, E. & Mateu, M. G. (1996). Antibody and host cell recognition of foot-and-mouth disease virus (serotype C) cleaved at the Arg-Gly-Asp (RGD) motif: a structural interpretation. Journal of General Virology 77, 257-264.[CrossRef] [Google Scholar]
  19. Hewat, E. A., Verdaguer, N., Fita, I., Blakemore, W., Brookes, S., King, A., Newman, J., Domingo, E., Mateu, M. G. & Stuart, D. I. (1997). Structure of the complex of an Fab fragment of a neutralizing antibody with foot-and-mouth disease virus: positioning of a highly mobile antigenic loop. EMBO Journal 16, 1492-1500.[CrossRef] [Google Scholar]
  20. Jackson, T., Sharma, A., Abu-Ghazaleh, R., Blakemore, W. E., Ellard, F. M., Simmons, D. L., Newman, J. W., Stuart, D. I. & King, A. M. (1997). Arginine-glycine-aspartic acid-specific binding by foot-and-mouth disease viruses to the purified integrin αvβ3 in vitro. Journal of Virology 71, 8357-8361. [Google Scholar]
  21. Jones, T. A., Zou, J.-Y., Cowan, S. W. & Kjeldgaard, M. (1991). Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallographica A47, 110-119. [Google Scholar]
  22. Lea, S., Hernández, J., Blakemore, W., Brocchi, E., Curry, S., Domingo, E., Fry, E., Abu-Ghazaleh, R., King, A., Newman, J., Stuart, D. & Mateu, M. G. (1993). Structure of a major immunogenic site on foot-and-mouth disease virus. Nature 362, 566-568.[CrossRef] [Google Scholar]
  23. Lea, S., Hernández, J., Blakemore, W., Brocchi, E., Curry, S., Domingo, E., Fry, E., Abu-Ghazaleh, R., King, A., Newman, J., Stuart, D. & Mateu, M. G. (1994). The structure and antigenicity of a type C foot-and-mouth disease virus. Structure 2, 123-139.[CrossRef] [Google Scholar]
  24. Lea, S., Abu-Ghazaleh, R., Blakemore, W., Curry, S., Fry, E., Jackson, T., King, A., Logan, D., Newman, J. & Stuart, D. (1995). Structural comparison of two strains of foot-and-mouth disease virus subtype O1 and a laboratory antigenic variant, G67. Structure 3, 571-580.[CrossRef] [Google Scholar]
  25. Logan, D., Abu-Ghazaleh, R., Blakemore, W., Curry, S., Jackson, T., King, A., Lea, S., Lewis, R., Newman, J., Parry, N., Rowlands, D., Stuart, D. & Fry, E. (1993). Structure of a major immunogenic site on foot-and-mouth disease virus. Nature 362, 566-568.[CrossRef] [Google Scholar]
  26. McCullough, K. C., De Simone, F., Brocchi, E., Capucci, L., Crowther, J. R. & Kihm, U. (1992). Protective immune response against foot-and-mouth disease. Journal of Virology 66, 1835-1840. [Google Scholar]
  27. Martı́nez, M. A., Hernández, J., Piccone, M. E., Palma, E. L., Domingo, E., Knowles, N. & Mateu, M. G. (1991). Two mechanisms of antigenic diversification of foot-and-mouth disease virus. Virology 184, 695-706.[CrossRef] [Google Scholar]
  28. Martı́nez, M. A., Verdaguer, N., Mateu, M. G. & Domingo, E. (1997). Evolution subverting essentiality: dispensability of the cell attachment Arg-Gly-Asp motif in multiply passaged foot-and-mouth disease virus . Proceedings of the National Academy of Sciences, USA 94, 6798-6802.[CrossRef] [Google Scholar]
  29. Mason, P. W., Rieder, E. & Baxt, B. (1994). RGD sequence of foot-and-mouth disease virus is essential for infecting cells via the natural receptor but can be bypassed by an antibody-dependent enhancement pathway. Proceedings of the National Academy of Sciences, USA 91, 1932-1936.[CrossRef] [Google Scholar]
  30. Mateu, M. G. (1995). Antibody recognition of picornaviruses and escape from neutralization: a structural view. Virus Research 38, 1-24.[CrossRef] [Google Scholar]
  31. Mateu, M. G., Rocha, E., Vicente, O., Vayreda, F., Navalpotro, C., Andreu, D., Pedroso, E., Giralt, E., Enjuanes, L. & Domingo, E. (1987). Reactivity with monoclonal antibodies of viruses from an episode of foot-and-mouth disease. Virus Research 8, 261-274.[CrossRef] [Google Scholar]
  32. Mateu, M. G., Da Silva, J. L., Rocha, E., De Brum, D. L., Alonso, A., Enjuanes, L., Domingo, E. & Barahona, H. (1988). Extensive antigenic heterogeneity of foot-and-mouth disease virus of serotype C. Virology 167, 113-124.[CrossRef] [Google Scholar]
  33. Mateu, M. G., Martı́nez, M. A., Rocha, E., Andreu, D., Parejo, J., Giralt, E., Sobrino, F. & Domingo, E. (1989). Implications of a quasispecies genome structure: effect of frequent, naturally occurring amino acid substitutions on the antigenicity of foot-and-mouth disease virus. Proceedings of the National Academy of Sciences, USA 86, 5883-5887.[CrossRef] [Google Scholar]
  34. Mateu, M. G., Martı́nez, M. A., Capucci, L., Andreu, D., Giralt, E., Sobrino, F., Brocchi, E. & Domingo, E. (1990). A single amino acid substitution affects multiple overlapping epitopes in the major antigenic site of foot-and-mouth disease virus of serotype C. Journal of General Virology 71, 629-637.[CrossRef] [Google Scholar]
  35. Mateu, M. G., Andreu, D., Carreño, C., Roig, X., Cairó, J. J., Camarero, J. A., Giralt, E. & Domingo, E. (1992). Non-additive effects of multiple amino acid substitutions on antigen–antibody recognition. European Journal of Immunology 22, 1385-1389.[CrossRef] [Google Scholar]
  36. Mateu, M. G., Valero, M. L., Andreu, D. & Domingo, E. (1996). Systematic replacement of amino acid residues within an Arg-Gly-Asp-containing loop of foot-and-mouth disease virus and effect on cell recognition. Journal of Biological Chemistry 271, 12814-12819.[CrossRef] [Google Scholar]
  37. Misbah, S. A., Spickett, G. P., Ryba, P. C., Hockaday, J. M., Kroll, J. S., Sherwood, C., Kurtz, J. B., Moxon, E. R. & Chapel, H. M. (1992). Chronic enteroviral meningoencephalitis in agammaglobulinemia: case report and literature review. Journal of Clinical Immunology 12, 266-270.[CrossRef] [Google Scholar]
  38. Navaza, J. (1994). AMoRe: an automated package for molecular replacement. Acta Crystallographica A50, 157-163. [Google Scholar]
  39. Neff, S., Sá-Carvalho, D., Rieder, E., Mason, P. W., Blystone, S. D., Brown, E. J. & Baxt, B. (1998). Foot-and-mouth disease virus virulent for cattle utilizes the integrin αvβ3 as its receptor. Journal of Virology 72, 3587-3594. [Google Scholar]
  40. Novella, I. S., Borrego, B., Mateu, M. G., Domingo, E., Giralt, E. & Andreu, D. (1993). Use of substituted and tandem-repeated peptides to probe the relevance of the highly conserved RGD tripeptide in the immune response against foot-and-mouth disease virus. FEBS Letters 330, 253-259.[CrossRef] [Google Scholar]
  41. Otwinowski, Z. & Minor, W. (1996). Processing of X-ray diffraction data collected in an oscillation mode. Methods in Enzymology 35, 307-326. [Google Scholar]
  42. Parry, N., Fox, G., Rowlands, D., Brown, F., Fry, E., Acharya, R., Logan, D. & Stuart, D. (1990). Structural and serological evidence for a novel mechanism of antigenic variation in foot-and-mouth disease virus. Nature 347, 569-572.[CrossRef] [Google Scholar]
  43. Pereira, H. G. (1977). Subtyping foot-and-mouth disease virus. Developments in Biological Standardization 35, 167-174. [Google Scholar]
  44. Pereira, H. G. (1981). Foot-and-mouth disease virus. In Virus Diseases of Food Animals, pp. 333-363. Edited by R. P. G. Gibbs. New York: Academic Press.
  45. Pfaff, E. (1997). Recognition sites of RGD-dependent integrins. In Integrin Ligand Interactions, pp. 101-121. Edited by J. A. Eble & K. Kühn. Austin, TX: R. G. Landes.
  46. Pfaff, E., Mussgay, M., Bohm, H. O., Schulz, G. E. & Schaller, H. (1982). Antibodies against a preselected peptide recognize and neutralize foot and mouth disease virus. EMBO Journal 1, 869-874. [Google Scholar]
  47. Rickaert, J. P., Ciccotti, G. & Berendsen, H. J. C. (1977). Numerical integration of cartesian equations of motions of a system with constraints: molecular dynamics of n-alkanes. Journal of Computational Physics 23, 327-341.[CrossRef] [Google Scholar]
  48. Rousel, A. & Cambillau, C. (1989). TURBO-Frodo. In Silicon Graphics Geometry Partners Directory, pp. 77–79. Mountain View, CA: Silicon Graphics.
  49. Rowlands, D. J., Clarke, B. E., Carroll, A. R., Brown, F., Nicholson, B. H., Bittle, J. L., Houghten, R. A. & Lerner, R. A. (1983). Chemical basis of antigenic variation in foot-and-mouth disease virus. Nature 306, 694-697.[CrossRef] [Google Scholar]
  50. Rueckert, R. R. (1996).Picornaviridae: the viruses and their replication. In Fields Virology, pp. 609-654. Edited by B. N. Fields, D. M. Knipe & P. M. Howley. Philadelphia: Lippincott–Raven.
  51. Sobrino, F., Dávila, M., Ortı́n, J. & Domingo, E. (1983). Multiple genetic variants arise in the course of replication of foot-and-mouth disease virus in cell culture. Virology 128, 310-318.[CrossRef] [Google Scholar]
  52. Strohmaier, K., Franze, R. & Adam, K.-H. (1982). Location and characterization of the antigenic portion of the FMDV immunizing protein. Journal of General Virology 59, 295-306.[CrossRef] [Google Scholar]
  53. Stura, E. A. & Wilson, I. A. (1992). Seeding techniques. In Crystallization of Nucleic Acids and Proteins. A Practical Approach, pp. 99-126. Edited by A. Ducruix & R. Giege. Oxford: IRL Press.
  54. Taboga, O., Tami, C., Carrillo, E., Núñez, J. I., Rodrı́guez, A., Saı́z, J. C., Blanco, E., Valero, M. L., Roig, X., Camarero, J. A., Andreu, D., Mateu, M. G., Giralt, E., Domingo, E., Sobrino, F. & Palma, E. L. (1997). A large-scale evaluation of peptide vaccines against foot-and-mouth disease: lack of solid protection in cattle and isolation of escape mutants. Journal of Virology 71, 2606-2614. [Google Scholar]
  55. Timoney, J. F., Gillespie, J. H., Scott, F. N. & Barlough, J. E. (1992). Foot-and-mouth disease. In Hagan and Bruner’s Microbiology and Infectious Diseases of Domestic Animals, pp. 647–667. Ithaca, NY: Cornell University Press.
  56. van Gunsteren, W. F., Billeter, S. R., Eising, A. A., Hünenberg, P. H., Krüger, P., Mark, A. E., Scott, W. R. P. & Tironi, I. G. (1996). Biomolecular simulation. In GROMOS96 Manual and User Guide. Zürich: Biomolecular Software.
  57. Verdaguer, N., Mateu, M. G., Andreu, D., Giralt, E., Domingo, E. & Fita, I. (1995). Structure of the major antigenic loop of foot-and-mouth disease virus complexed with a neutralizing antibody: direct involvement of the Arg-Gly-Asp motif in the interaction. EMBO Journal 14, 1690-1696. [Google Scholar]
  58. Verdaguer, N., Mateu, M. G., Bravo, J., Domingo, E. & Fita, I. (1996). Induced pocket to accommodate the cell attachment Arg-Gly-Asp motif in a neutralizing antibody against foot-and-mouth disease virus. Journal of Molecular Biology 256, 364-376.[CrossRef] [Google Scholar]
  59. Verdaguer, N., Fita, I., Domingo, E. & Mateu, M. G. (1997). Efficient neutralization of foot-and-mouth disease virus by monovalent antibody binding. Journal of Virology 71, 9813-9816. [Google Scholar]
  60. Verdaguer, N., Sevilla, N., Valero, M. L., Stuart, D., Brocchi, E., Andreu, D., Giralt, E., Domingo, E., Mateu, M. G. & Fita, I. (1998). A similar pattern of interaction for different antibodies with a major antigenic site of foot-and-mouth disease virus: implications for intratypic antigenic variation. Journal of Virology 72, 739-748. [Google Scholar]
  61. Verdaguer, N., Schoehn, G., Ochoa, W. F., Fita, I., Brookes, S., King, A., Domingo, E., Mateu, M. G., Stuart, D. & Hewat, E. A. (1999). Flexibility of the major antigenic loop of foot-and-mouth disease virus bound to a Fab fragment of a neutralizing antibody: structure and neutralization. Virology 255, 260-268.[CrossRef] [Google Scholar]
  62. Villaverde, A., Martı́nez, M. A., Sobrino, F., Dopazo, J., Moya, A. & Domingo, E. (1991). Fixation of mutations at the VP1 gene of foot-and-mouth disease virus. Can quasispecies define a transient molecular clock? Gene 103, 147-153.[CrossRef] [Google Scholar]
/content/journal/jgv/10.1099/0022-1317-81-6-1495
Loading
/content/journal/jgv/10.1099/0022-1317-81-6-1495
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error