Structural Basis for Allosteric Ligand Recognition in the Human CC Chemokine Receptor 7

Cell. 2019 Aug 22;178(5):1222-1230.e10. doi: 10.1016/j.cell.2019.07.028.


The CC chemokine receptor 7 (CCR7) balances immunity and tolerance by homeostatic trafficking of immune cells. In cancer, CCR7-mediated trafficking leads to lymph node metastasis, suggesting the receptor as a promising therapeutic target. Here, we present the crystal structure of human CCR7 fused to the protein Sialidase NanA by using data up to 2.1 Å resolution. The structure shows the ligand Cmp2105 bound to an intracellular allosteric binding pocket. A sulfonamide group, characteristic for various chemokine receptor ligands, binds to a patch of conserved residues in the Gi protein binding region between transmembrane helix 7 and helix 8. We demonstrate how structural data can be used in combination with a compound repository and automated thermal stability screening to identify and modulate allosteric chemokine receptor antagonists. We detect both novel (CS-1 and CS-2) and clinically relevant (CXCR1-CXCR2 phase-II antagonist Navarixin) CCR7 modulators with implications for multi-target strategies against cancer.

Keywords: CCR7; G protein-coupled receptors; allosteric modulation; cancer; chemokine receptors; crystal structure; lymph node metastasis; membrane proteins; structure-based drug screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Binding Sites
  • Crystallography, X-Ray
  • Humans
  • Ligands*
  • Molecular Dynamics Simulation
  • Neuraminidase / genetics
  • Neuraminidase / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, CCR2 / chemistry
  • Receptors, CCR2 / metabolism
  • Receptors, CCR7 / antagonists & inhibitors
  • Receptors, CCR7 / genetics
  • Receptors, CCR7 / metabolism*
  • Recombinant Fusion Proteins / biosynthesis
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / isolation & purification


  • CCR2 protein, human
  • Ligands
  • Receptors, CCR2
  • Receptors, CCR7
  • Recombinant Fusion Proteins
  • Neuraminidase