Structural determinants of CCR5 recognition and HIV-1 blockade in RANTES

Vanessa Nardese, Renato Longhi, Simona Polo, Francesca Sironi, Cinzia Arcelloni, Rita Paroni, Claudio Desantis, Paolo Sarmientos, Menico Rizzi, Martino Bolognesi, Vincenzo Pavone, Paolo Lusso

Research output: Contribution to journalArticle

Abstract

Certain chemokines act as natural antagonists of human immunodeficiency virus (HIV) by blocking key viral coreceptors, such as CCR5 and CXCR4, on the surface of susceptible cells. Elucidating the structural determinants of the receptor-binding and HIV-inhibitory functions of these chemokines is essential for the rational design of derivative molecules of therapeutic value. Here, we identify the structural determinants of CCR5 recognition and antiviral activity of the CC chemokine RANTES, showing that critical residues form a solvent-exposed hydrophobic patch on the surface of the molecule. Moreover, we demonstrate that the biological function is critically dependent on dimerization, resulting in the exposure of a large (∼180 Å2), continuous hydrophobic surface. Relevant to the development of novel therapeutic approaches, we designed a retroinverted RANTES peptide mimetic that maintained both HIV- and chemotaxis-antagonistic functions.

Original languageEnglish
Pages (from-to)611-615
Number of pages5
JournalNature Structural Biology
Volume8
Issue number7
DOIs
Publication statusPublished - 2001

ASJC Scopus subject areas

  • Biochemistry
  • Structural Biology
  • Genetics

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    Nardese, V., Longhi, R., Polo, S., Sironi, F., Arcelloni, C., Paroni, R., Desantis, C., Sarmientos, P., Rizzi, M., Bolognesi, M., Pavone, V., & Lusso, P. (2001). Structural determinants of CCR5 recognition and HIV-1 blockade in RANTES. Nature Structural Biology, 8(7), 611-615. https://doi.org/10.1038/89653