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.
Kathrin Jaeger  1 ,  Steffen Bruenle  1 ,  Tobias Weinert  1 ,  Wolfgang Guba  2 ,  Jonas Muehle  3 ,  Takuya Miyazaki  4 ,  Martin Weber  2 ,  Antonia Furrer  1 ,  Noemi Haenggi  2 ,  Tim Tetaz  2 ,  Chia-Ying Huang  5 ,  Daniel Mattle  3 ,  Jean-Marie Vonach  2 ,  Alain Gast  2 ,  Andreas Kuglstatter  2 ,  Markus G Rudolph  2 ,  Przemyslaw Nogly  1 ,  Joerg Benz  2 ,  Roger J P Dawson  6 ,  Joerg Standfuss  7
Affiliations
  • 1. Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institute, Villigen PSI.
  • 2. Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland.
  • 3. Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institute, Villigen PSI; Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland.
  • 4. Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland; Chugai Pharmaceutical Co., Ltd., Research Division, Kamakura Research Labs, Kamakura, Kanagawa, Japan.
  • 5. Macromolecular Crystallography, Swiss Light Source, Paul Scherrer Institute, 5232 Villigen PSI, Switzerland.
  • 6. Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland. Electronic address: [email protected].
  • 7. Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institute, Villigen PSI. Electronic address: [email protected].
PMID: 31442409 DOI: 10.1016/j.cell.2019.07.028
Abstract

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.
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