Journal
MOLECULAR CELL
Volume 72, Issue 1, Pages 48-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2018.08.009
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Funding
- University of Pittsburgh
- NIH (Maximizing Investigators' Research Award [MIRA]) [R351R35GM128641]
- Biomedical Research Council (A*STAR)
- National Natural Science Foundation of China [31770791, 315707410]
- Southern University of Science and Technology
- Recruitment Program of Global Youth Experts of China
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The signaling of prostaglandin D-2 (PGD(2)) 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 PGD(2), which differs significantly from the binding pose and binding environment of lysophospholipids and endocannabinoids, revealing a new mechanism for lipid recognition by GPCRs.
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