Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

X-ray structure of a minor group human rhinovirus bound to a fragment of its cellular receptor protein

Nature Structural & Molecular Biology volume 11, pages 429–434 (2004)Cite this article

Abstract

Although many viral receptors have been identified, the ways in which they interact with their cognate viruses are not understood at the molecular level. We have determined the X-ray structure of a complex between calcium-containing modules of the very low-density lipoprotein receptor and the minor group human rhinovirus HRV2. The receptor binds close to the icosahedral five-fold vertex, with only one module per virus protomer. The binding face of this module is defined by acidic calcium-chelating residues and, in particular, by an exposed tryptophan that is highly conserved. The attachment site on the virus involves only residues from VP1, particularly a lysine strictly conserved in all minor group HRVs. The disposition of the attached ligand-binding repeats around the five-fold axis, together with the proximity of the N- and C-terminal ends of adjacent modules, suggests that more than one repeat in a single receptor molecule might attach simultaneously.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Scheme of the modular organization of members of the LDLR family.
Figure 2: Three-dimensional structure of the V23–HRV2 complex.
Figure 3: Interactions between the V3 module from VLDLR and HRV2.
Figure 4: A concatamer with five copies of V3 protects HeLa cells against infection by all minor group HRVs.

Similar content being viewed by others

Accession codes

Accessions

Protein Data Bank

References

  1. Fry, E.E. et al. The structure and function of a foot-and-mouth disease virus–oligosaccharide receptor complex. EMBO J. 18, 543–554 (1999).

    Article  CAS  Google Scholar 

  2. Greve, J.M. et al. The major human rhinovirus receptor is ICAM-1. Cell 56, 839–847 (1989).

    Article  CAS  Google Scholar 

  3. Staunton, D.E. et al. A cell adhesion molecule, ICAM-1, is the major surface receptor for rhinoviruses. Cell 56, 849–853 (1989).

    Article  CAS  Google Scholar 

  4. Hofer, F. et al. Members of the low density lipoprotein receptor family mediate cell entry of a minor-group common cold virus. Proc. Natl. Acad. Sci. USA 91, 1839–1842 (1994).

    Article  CAS  Google Scholar 

  5. Marlovits, T.C., Abrahamsberg, C. & Blaas, D. Very-low-density lipoprotein receptor fragment shed from HeLa cells inhibits human rhinovirus infection. J. Virol. 72, 10246–10250 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Herz, J. & Marschang, P. Coaxing the LDL receptor family into the fold. Cell 112, 289–292 (2003).

    Article  CAS  Google Scholar 

  7. Fass, D., Blacklow, S., Kim, P.S. & Berger, J.M. Molecular basis of familial hypercholesterolaemia from structure of LDL receptor module. Nature 388, 691–693 (1997).

    Article  CAS  Google Scholar 

  8. Rudenko, G. et al. Structure of the LDL receptor extracellular domain at endosomal pH. Science 298, 2353–2358 (2002).

    Article  CAS  Google Scholar 

  9. Davis, C.G. et al. Acid-dependent ligand dissociation and recycling of LDL receptor mediated by growth factor homology region. Nature 326, 760–765 (1987).

    Article  CAS  Google Scholar 

  10. Nykjaer, A. & Willnow, T.E. The low-density lipoprotein receptor gene family: a cellular Swiss army knife? Trends Cell Biol. 12, 273–280 (2002).

    Article  CAS  Google Scholar 

  11. Rossmann, M.G. et al. Structure of a human common cold virus and functional relationship to other picornaviruses. Nature 317, 145–153 (1985).

    Article  CAS  Google Scholar 

  12. Badger, J. et al. Structural analysis of a series of antiviral agents complexed with human rhinovirus 14. Proc. Natl. Acad. Sci. USA 85, 3304–3308 (1988).

    Article  CAS  Google Scholar 

  13. Hewat, E.A. et al. The cellular receptor to human rhinovirus 2 binds around the 5-fold axis and not in the canyon: a structural view. EMBO J. 19, 6317–6325 (2000).

    Article  CAS  Google Scholar 

  14. Neumann, E., Moser, R., Snyers, L., Blaas, D. & Hewat, E.A. A cellular receptor of human rhinovirus type 2, the very-low-density lipoprotein receptor, binds to two neighboring proteins of the viral capsid. J. Virol. 77, 8504–8511 (2003).

    Article  CAS  Google Scholar 

  15. Dolmer, K., Huang, W. & Gettins, P.G. NMR solution structure of complement-like repeat CR3 from the low density lipoprotein receptor-related protein. Evidence for specific binding to the receptor binding domain of human α(2)-macroglobulin. J. Biol. Chem. 275, 3264–3269 (2000).

    Article  CAS  Google Scholar 

  16. Daly, N.L., Scanlon, M.J., Djordjevic, J.T., Kroon, P.A. & Smith, R. Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor. Proc. Natl. Acad. Sci. USA 92, 6334–6338 (1995).

    Article  CAS  Google Scholar 

  17. Daly, N.L., Djordjevic, J.T., Kroon, P.A. & Smith, R. Three-dimensional structure of the second cysteine-rich repeat from the human low-density lipoprotein receptor. Biochemistry 34, 14474–14481 (1995).

    Article  CAS  Google Scholar 

  18. Huang, W., Dolmer, K. & Gettins, P.G.W. NMR solution structure of complement-like repeat CR8 from the low density lipoprotein receptor-related protein. J. Biol. Chem. 274, 14130–14136 (1999).

    Article  CAS  Google Scholar 

  19. Verdaguer, N., Blaas, D. & Fita, I. Structure of human rhinovirus serotype 2 (HRV2). J. Mol. Biol. 300, 1179–1194 (2000).

    Article  CAS  Google Scholar 

  20. Rossmann, M.G. Viral cell recognition and entry. Protein Sci. 3, 1712–1725 (1994).

    Article  CAS  Google Scholar 

  21. Lo Conte, L., Chothia, C. & Janin, J. The atomic structure of protein-protein recognition sites. J. Mol. Biol. 285, 2177–2198 (1999).

    Article  CAS  Google Scholar 

  22. Fox, G. et al. The cell attachment site on foot-and-mouth disease virus includes the amino acid sequence RGD (arginine-glycine-aspartic acid). J. Gen. Virol. 70, 625–637 (1989).

    Article  CAS  Google Scholar 

  23. Appleyard, G. et al. Neutralization epitopes of human rhinovirus type 2. J. Gen. Virol. 71, 1275–1282 (1990).

    Article  CAS  Google Scholar 

  24. Vlasak, M., Blomqvist, S., Hovi, T., Hewat, E. & Blaas, D. Sequence and structure of human rhinoviruses reveal the basis of receptor discrimination. J. Virol. 77, 6923–6930 (2003).

    Article  CAS  Google Scholar 

  25. Duechler, M., Ketter, S., Skern, T., Kuechler, E. & Blaas, D. Rhinoviral receptor discrimination: mutational changes in the canyon regions of human rhinovirus types 2 and 14 indicate a different site of interaction. J. Gen. Virol. 74, 2287–2291 (1993).

    Article  CAS  Google Scholar 

  26. Brabec, M., Baravalle, G., Blaas, D. & Fuchs, R. Conformational changes, plasma membrane penetration, and infection by human rhinovirus type 2: role of receptors and low pH. J. Virol. 77, 5370–5377 (2003).

    Article  CAS  Google Scholar 

  27. Oka, K. et al. Mouse very-low-density-lipoprotein receptor (VLDLR) cDNA cloning, tissue-specific expression and evolutionary relationship with the low-density-lipoprotein receptor. Eur. J. Biochem. 224, 975–982 (1994).

    Article  CAS  Google Scholar 

  28. Reithmayer, M., Reischl, A., Snyers, L. & Blaas, D. Species-specific receptor recognition by a minor-group human rhinovirus (HRV): HRV serotype 1A distinguishes between the murine and the human low-density lipoprotein receptor. J. Virol. 76, 6957–6965 (2002).

    Article  CAS  Google Scholar 

  29. Marlovits, T.C. et al. Recombinant soluble low density lipoprotein receptor fragment inhibits minor group rhinovirus infection in vitro . FASEB J. 12, 695–703 (1998).

    Article  CAS  Google Scholar 

  30. Marlovits, T.C., Abrahamsberg, C. & Blaas, D. Soluble LDL minireceptors. Minimal structure requirements for recognition of minor group human rhinovirus. J. Biol. Chem. 273, 33835–33840 (1998).

    Article  CAS  Google Scholar 

  31. Goldstein, J.L. & Brown, M.S. Binding and degradation of low density lipoproteins by cultured human fibroblasts. Comparison of cells from a normal subject and from a patient with homozygous familial hypercholesterolemia. J. Biol. Chem. 249, 5153–5162 (1974).

    CAS  PubMed  Google Scholar 

  32. Ronacher, B., Marlovits, T.C., Moser, R. & Blaas, D. Expression and folding of human very-low-density lipoprotein receptor fragments: neutralization capacity toward human rhinovirus HRV2. Virology 278, 541–550 (2000).

    Article  CAS  Google Scholar 

  33. Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307–326 (1997).

    Article  CAS  Google Scholar 

  34. Brünger, A.T. X-PLOR: A System for X-ray Crystallography and NMR (Yale Univ. Press, New Haven, 1993).

    Google Scholar 

  35. Diprose, J.M. et al., translocation portals for the substrates and products of a viral transcription complex: the bluetonge virus core. EMBO J. 20, 7229–7239 (2001).

    Article  CAS  Google Scholar 

  36. Roussel, A. & Cambillau, C. Turbo-Frodo. In Silicon Graphics Geometry Partners Directory 77–79 (Silicon Graphics, Mountain View, California, USA, 1989).

    Google Scholar 

  37. Jones, T.A., Zou, J.Y., Cowan, S.W. & Kjeldgaard . Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallogr. A 47, 110–119 (1991).

    Article  Google Scholar 

  38. Brünger, A.T. et al. Crystallography & NMR system: a new software suite for macromolecular structure determination. Acta Crystallogr. D 54, 905–921 (1998).

    Article  Google Scholar 

  39. Laskowski, R.A., MacArthur, M.W., Moss, D.S. & Thornton, J.M. PROCHECK: programs for checking the quality of protein structures. J. Appl. Cryst. 26, 283–291 (1993).

    Article  CAS  Google Scholar 

  40. Herdy, B., Snyers, L., Reithmayer, M., Hinterdorfer, P. & Blaas, D. Identification of the HRV1A binding site on murine LDLR using human-mouse chimeras. J. Virol. (in the press).

Download references

Acknowledgements

This work was supported by grants BIO2002-00517 and BIO2002-04419 of Comision Interministerial de Ciencia y Tecnología to N.V and I.F, respectively, and by the Austrian Science Foundation, grant number P-14503, to D.B. Data were collected at the European Molecular Biology Laboratory protein crystallography beamlines ID14.4 and ID29 at European Synchrotron Radiation Facility (ESRF, Grenoble) within a Block Allocation Group (BAG Barcelona). Financial support was provided by the ESRF and by grant HPRI-CT-1999-00022 of the European Union. We thank I. Goesler for expert technical assistance, E. Hewat for sending us the electron microscopy maps before publication and M.G. Rossmann, T. Skern and P.C. Loewen for critically reading the manuscript.

Author information

Authors and Affiliations

  1. Institut de Biologia Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, Jordi Girona 18-26, Barcelona, E-08034, Spain

    Nuria Verdaguer & Ignacio Fita

  2. University Departments at the Vienna Biocenter, Department of Medical Biochemistry, Max F. Perutz Laboratories, University of Vienna, Dr. Bohr Gasse 9/3, Vienna, A-1030, Austria

    Manuela Reithmayer, Rosita Moser & Dieter Blaas

Authors
  1. Nuria Verdaguer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ignacio Fita
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Manuela Reithmayer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rosita Moser
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dieter Blaas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nuria Verdaguer.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Verdaguer, N., Fita, I., Reithmayer, M. et al. X-ray structure of a minor group human rhinovirus bound to a fragment of its cellular receptor protein. Nat Struct Mol Biol 11, 429–434 (2004). https://doi.org/10.1038/nsmb753

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsmb753

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing