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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.