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

Author:
Jaeger, Kathrin, Bruenle, Steffen, Weinert, Tobias, Guba, Wolfgang, Muehle, Jonas, Miyazaki, Takuya, Weber, Martin, Furrer, Antonia, Haenggi, Noemi, Tetaz, Tim, Huang, Chia-Ying, Mattle, Daniel, Vonach, Jean-Marie, Gast, Alain, Kuglstatter, Andreas, Rudolph, Markus G., Nogly, Przemyslaw, Benz, Joerg, Dawson, Roger J.P., Standfuss, Joerg
Source:
Cell 2019 v.178 no.5 pp. 1222-1230.e10
ISSN:
0092-8674
Subject:
CCR7 receptor, antagonists, automation, crystal structure, immunity, ligands, lymph nodes, metastasis, neoplasms, protein binding, screening, sialidase, therapeutics, thermal stability
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.
Agid:
6593147