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

K. Jaeger | Zendy; S. Bruenle | Zendy; Tobias Weinert | Zendy; Wolfgang Guba | Zendy; J. Muehle | Zendy; Takuya Miyazaki | Zendy; Martin S. Weber | Zendy; Antonia Furrer | Zendy; Noemi Haenggi | Zendy; Tim Tetaz | Zendy; ChiaYing Huang | Zendy; Daniel Mattle | Zendy; Jean-Marie Vonach | Zendy; Alain Gast | Zendy; A. Kuglstatter | Zendy; M.G. Rudolph | Zendy; Przemysław Nogły | Zendy; J. Benz | Zendy; Roger Dawson | Zendy; J. Standfuss | Zendy

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

Author(s) -

K. Jaeger,

S. Bruenle,

Tobias Weinert,

Wolfgang Guba,

J. Muehle,

Takuya Miyazaki,

Martin S. Weber,

Antonia Furrer,

Noemi Haenggi,

Tim Tetaz,

ChiaYing Huang,

Daniel Mattle,

Jean-Marie Vonach,

Alain Gast,

A. Kuglstatter,

M.G. Rudolph,

Przemysław Nogły,

J. Benz,

Roger Dawson,

J. Standfuss

Publication year - 2019

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2019.07.028

Subject(s) - c c chemokine receptor type 7 , allosteric regulation , biology , ccl21 , chemokine receptor , cc chemokine receptors , microbiology and biotechnology , g protein coupled receptor , cxc chemokine receptors , receptor , biochemistry , chemokine

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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