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  • The EMBO Journal (1997) 16, 6996 - 7007
  • doi:10.1093/emboj/16.23.6996

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. Crump1, Jiang-Hong Gong2, Pius Loetscher3, Krishna Rajarathnam1, Ali Amara4, Fernando Arenzana-Seisdedos4, Jean-Louis Virelizier4, Marco Baggiolini3, Brian D. Sykes1 and Ian Clark-Lewis2

  1. Protein Engineering Network of Centers of Excellence (PENCE) and Department of Biochemistry, 713 Heritage Medical Research Center, University of Alberta, Edmonton, Alberta, Canada T6G 2S2
  2. Biomedical Research Centre and Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada, V6T 1Z3
  3. Theodor-Kocher Institute, University of Bern, PO Box 3000, Bern 9, Switzerland
  4. Unite d'Immunologie Virale, Institut Pasteur, 75724 Paris Cedex 15, France

Received 31 July 1997; Revised 28 August 1997

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.

  • Keywords:

    • chemokines,
    • G-protein coupled receptors,
    • nuclear magnetic resonance spectroscopy,
    • protein synthesis,
    • stromal cell-derived factor-1