Hot topics: Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists

CC chemokine receptor 2 (CCR2) is one of 19 members of the chemokine receptor subfamily of human class A G-protein-coupled receptors. CCR2 is expressed on monocytes, immature dendritic cells, and T-cell subpopulations, and mediates their migration towards endogenous CC chemokine ligands such as CCL2. To aid drug discovery efforts, this article solves a structure of CCR2 in a ternary complex with an orthosteric (BMS-681) and allosteric (CCR2-RA-[R]) antagonist. BMS-681 inhibits chemokine binding by occupying the orthosteric pocket of the receptor in a previously unseen binding mode. CCR2-RA-[R] binds in a novel, highly druggable pocket that is the most intracellular allosteric site observed in class A G-protein-coupled receptors so far; this site spatially overlaps the G-protein-binding site in homologous receptors.

[1] Zheng et al. (2016). Nature 540(7633):458-461. Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists. [PMID: 27926736].

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