Hot topics: Intracellular allosteric antagonism of the CCR9 receptor

Chemokines and their GPCR receptors are important drug targets in a broad range of diseases due to their role in immune defence (by controlling migration, activation and survival of immune cells), viral entry, tumour growth and metastasis. This article presents the crystal structure of the CCR9 receptor in complex with vercirnon (GtoPdb ligand ID: 9046) at 2.8Å resolution. Remarkably, vercirnon binds to the intracellular side of the receptor, exerting allosteric antagonism and preventing G-protein coupling. This binding site explains the need for relatively lipophilic ligands and describes another example of an allosteric site on G-protein-coupled receptors that can be targeted for drug design, not only at CCR9, but potentially extending to other chemokine receptors.

[1] Oswald et al. (2016). Nature 540(7633):462-465. Intracellular allosteric antagonism of the CCR9 receptor. [PMID: 27926729]

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