2. Academic Validation
  3. Structural Basis for Allosteric Ligand Recognition in the Human CC Chemokine Receptor 7

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

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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