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

Clicks: 274
ID: 13626
2019
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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.
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jaeger2019structuralcell Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors 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;
Journal Cell
Year 2019
DOI
S0092-8674(19)30795-0
URL
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