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

Publication date: 22 August 2019Source: Cell, Volume 178, Issue 5Author(s): Kathrin Jaeger, Steffen Bruenle, Tobias Weinert, Wolfgang Guba, Jonas Muehle, Takuya Miyazaki, Martin Weber, Antonia Furrer, Noemi Haenggi, Tim Tetaz, Chia-Ying Huang, Daniel Mattle, Jean-Marie Vonach, Alain Gast, Andreas Kuglstatter, Markus G. Rudolph, Przemyslaw Nogly, Joerg Benz, Roger J.P. Dawson, Joerg StandfussSummaryThe 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.Graphical Abstract
Source: Cell - Category: Cytology Source Type: research