Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1

Matthew P. Crump, Jiang Hong Gong, Pius Loetscher, Krishna Rajarathnam, Ali Amara, Fernando Arenzana-Seisdedos, Jean Louis Virelizier, Marco Baggiolini, Brian D. Sykes, Ian Clark-Lewis

Research output: Contribution to journalArticle

595 Scopus citations

Abstract

The three-dimensional structure of stromal cell-derived factor-1 (SDF-1) was determined by NMR spectroscopy. SDF-1 is a monomer with a disordered N-terminal region (residues 1-8), and differs from other chemokines in the packing of the hydrophobic core and surface charge distribution. Results with analogs showed that the N-terminal eight residues formed an important receptor binding site; however, only Lys-1 and Pro-2 were directly involved in receptor activation. Modification to Lys-1 and/or Pro-2 resulted in loss of activity, but generated potent SDF-1 antagonists. Residues 12-17 of the loop region, which we term the RFFESH motif, unlike the N-terminal region, were well defined in the SDF-1 structure. The RFFESH formed a receptor binding site, which we propose to be an important initial docking site of SDF-1 with its receptor. The ability of the SDF-1 analogs to block HIV-1 entry via CXCR4, which is a HIV-1 coreceptor for the virus in addition to being the receptor for SDF-1, correlated with their affinity for CXCR4. Activation of the receptor is not required for HIV-1 inhibition.

Original languageEnglish (US)
Pages (from-to)6996-7007
Number of pages12
JournalEMBO Journal
Volume16
Issue number23
DOIs
StatePublished - Dec 1 1997

Keywords

  • Chemokines
  • G-protein coupled receptors
  • Nuclear magnetic resonance spectroscopy
  • Protein synthesis
  • Stromal cell-derived factor-1

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Crump, M. P., Gong, J. H., Loetscher, P., Rajarathnam, K., Amara, A., Arenzana-Seisdedos, F., Virelizier, J. L., Baggiolini, M., Sykes, B. D., & Clark-Lewis, I. (1997). Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1. EMBO Journal, 16(23), 6996-7007. https://doi.org/10.1093/emboj/16.23.6996