1. Structural Basis for Allosteric Ligand Recognition in the Human CC Chemokine Receptor 7.
- Author
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Jaeger K, Bruenle S, Weinert T, Guba W, Muehle J, Miyazaki T, Weber M, Furrer A, Haenggi N, Tetaz T, Huang CY, Mattle D, Vonach JM, Gast A, Kuglstatter A, Rudolph MG, Nogly P, Benz J, Dawson RJP, and Standfuss J
- Subjects
- Allosteric Regulation, Binding Sites, Crystallography, X-Ray, Humans, Molecular Dynamics Simulation, Neuraminidase genetics, Neuraminidase metabolism, Protein Binding, Protein Structure, Tertiary, Receptors, CCR2 chemistry, Receptors, CCR2 metabolism, Receptors, CCR7 antagonists & inhibitors, Receptors, CCR7 genetics, Recombinant Fusion Proteins biosynthesis, Recombinant Fusion Proteins chemistry, Recombinant Fusion Proteins isolation & purification, Ligands, Receptors, CCR7 metabolism
- 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., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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