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Structures of the Human PGD2 Receptor CRTH2 Reveal Novel Mechanisms for Ligand Recognition

Wang, Lei, Yao, Dandan, Deepak, R.N.V. Krishna, Liu, Heng, Xiao, Qingpin, Fan, Hao, Gong, Weimin, Wei, Zhiyi, Zhang, Cheng
Molecular cell 2018 v.72 no.1 pp. 48-59.e4
G-protein coupled receptors, antagonists, asthma, cannabinoids, clinical trials, crystal structure, humans, inflammation, ligands, prostaglandins, therapeutics
The signaling of prostaglandin D2 (PGD2) through G-protein-coupled receptor (GPCR) CRTH2 is a major pathway in type 2 inflammation. Compelling evidence suggests the therapeutic benefits of blocking CRTH2 signaling in many inflammatory disorders. Currently, a number of CRTH2 antagonists are under clinical investigation, and one compound, fevipiprant, has advanced to phase 3 clinical trials for asthma. Here, we present the crystal structures of human CRTH2 with two antagonists, fevipiprant and CAY10471. The structures, together with docking and ligand-binding data, reveal a semi-occluded pocket covered by a well-structured amino terminus and different binding modes of chemically diverse CRTH2 antagonists. Structural analysis suggests a ligand entry port and a binding process that is facilitated by opposite charge attraction for PGD2, which differs significantly from the binding pose and binding environment of lysophospholipids and endocannabinoids, revealing a new mechanism for lipid recognition by GPCRs.