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.

Abstract

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

Substances

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