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 J. 1997 Dec 1;16(23):6996-7007. doi: 10.1093/emboj/16.23.6996.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacology
  • Binding Sites
  • Chemokine CXCL12
  • Chemokines / agonists
  • Chemokines / antagonists & inhibitors
  • Chemokines / chemistry*
  • Chemokines / pharmacology
  • Chemokines, CXC*
  • HIV-1 / drug effects*
  • Models, Biological
  • Models, Molecular
  • Molecular Sequence Data
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Binding
  • Protein Conformation
  • Receptors, CXCR4 / drug effects*
  • Sequence Homology, Amino Acid
  • Structure-Activity Relationship
  • Virus Replication / drug effects


  • Anti-HIV Agents
  • Chemokine CXCL12
  • Chemokines
  • Chemokines, CXC
  • Receptors, CXCR4