The Structure of CCR7 Reveals a Binding Pocket for Antagonists

Due to its association with metastasis to the lymph nodes in colorectal cancer, the transmembrane protein CC chemokine receptor 7 (CCR7) represents an interesting therapeutic target. Jaeger, Bruenle, and colleagues elucidated the structure of CCR7 bound to the allosteric antagonist Cmp2105. Crystallization of CCR7 was enabled by its fusion with the 52.8 kDa-protein Sialidase NanA, and crystals diffracted to a resolution of 2.1 Å. The addition of Cmp2105 strongly stabilized CCR7, and the measured IC₅₀ of Cmp2105 in membrane-based competition assays using radiolabeled CCL19 (CCR7′s native ligand) was 35 nM. Unexpectedly, the structure revealed that Cmp2105 bound in an intracellular pocket between the ends of the transmembrane (TM) helices TM1, TM2, TM3, and TM6 and the loop between TM7 and helix 8 (H8), and two of Cmp2105′s amino groups formed hydrogen bonds with Asp94. Comparisons with the structures of CX3CL1 and CCR2 showed that Cmp2105 stabilized an inactive conformation of CCR7, consistent with its inhibitory effects. A 3-D shape similarity search of 2.3 million compounds using Cmp2105 as a seed revealed 293 compounds with similar 3-D pharmacophores. The two best matches were determined by thermal stability assays; one of the two was navarixin (also known as SCH-527123 or MK-7123), a CXCR1 and CXCR2 antagonist exhibiting high potency and bioavailability. Molecular docking demonstrated marked similarities between the binding mode of navarixin and that of Cmp2105, including interactions with the TM7–H8 motif and Asp94. Due to its observed antimetastatic activity in colorectal and some other cancers, navarixin is currently being tested in phase II clinical trials. It is possible that, in addition to its known antagonism of CXCR1 and CXCR2, navarixin's utility in preventing metastasis may be attributable to CCR7 antagonism. Additionally, the discovery of the structure of CCR7 bound to an antagonist and the drug screen described in this study provide a platform for further investigations of possible CCR7 antagonists.

Jaeger K, Bruenle S, Weinert T, Guba W, Muehle J, Miyazaki T, et al. Structural basis for allosteric ligand recognition in the human CC chemokine receptor 7. Cell 2019:178;1222–30.E10.

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