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

• Published in: Molecular cell Vol. 72; no. 1; pp. 48 - 59.e4
• Main Authors: Wang, Lei, Yao, Dandan, Deepak, R.N.V. Krishna, Liu, Heng, Xiao, Qingpin, Fan, Hao, Gong, Weimin, Wei, Zhiyi, Zhang, Cheng
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.10.2018; Cell Press - Elsevier
• Subjects: asthma; CRTH2; fevipiprant; GPCR; ligand binding; lipids; prostaglandin D2; structure; lipids; prostaglandin D2; GPCR; CRTH2; asthma; structure; ligand binding; fevipiprant
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2018.08.009

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. [Display omitted] •Crystal structures of antagonist-bound human CRTH2 are solved•A well-structured N terminus covers ligand binding pocket•Conserved and divergent binding features of CRTH2 antagonists are revealed•A multiple-step binding process of prostaglandin D2 is proposed Wang et al. reported crystal structures of antagonist-bound human CRTH2 as a new asthma drug target. Chemically diverse antagonists occupy a similar semi-occluded pocket with distinct binding modes. Structural analysis suggests a potential ligand entry port and an opposite charge attraction-facilitated binding process for the endogenous CRTH2 ligand prostaglandin D2.