Structural analysis of a novel small molecule ligand bound to the CXCL12 chemokine

J Med Chem. 2014 Nov 26;57(22):9693-9. doi: 10.1021/jm501194p. Epub 2014 Nov 13.


CXCL12 binds to CXCR4, promoting both chemotaxis of lymphocytes and metastasis of cancer cells. We previously identified small molecule ligands that bind CXCL12 and block CXCR4-mediated chemotaxis. We now report a 1.9 Å resolution X-ray structure of CXCL12 bound by such a molecule at a site normally bound by sY21 of CXCR4. The complex structure reveals binding hot spots for future inhibitor design and suggests a new approach to targeting CXCL12-CXCR4 signaling in drug discovery.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Binding Sites
  • Chemokine CXCL12 / chemistry*
  • Chemotaxis
  • Crystallography, X-Ray / methods*
  • Drug Design
  • Humans
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, CXCR4 / chemistry*
  • Signal Transduction
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • CXCL12 protein, human
  • CXCR4 protein, human
  • Chemokine CXCL12
  • Ligands
  • Receptors, CXCR4