Structures of the Human PGD 2 Receptor CRTH2 Reveal Novel Mechanisms for Ligand Recognition

Mol Cell. 2018 Oct 4;72(1):48-59.e4. doi: 10.1016/j.molcel.2018.08.009. Epub 2018 Sep 13.

Abstract

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.

Keywords: CRTH2; GPCR; asthma; fevipiprant; ligand binding; lipids; prostaglandin D2; structure.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbazoles / chemistry
  • Humans
  • Indoleacetic Acids / chemistry
  • Ligands
  • Molecular Docking Simulation
  • Prostaglandin D2 / chemistry*
  • Prostaglandin D2 / genetics
  • Protein Binding
  • Pyridines / chemistry
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Receptors, G-Protein-Coupled / chemistry*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, Immunologic / antagonists & inhibitors
  • Receptors, Immunologic / chemistry*
  • Receptors, Immunologic / genetics
  • Receptors, Prostaglandin / antagonists & inhibitors
  • Receptors, Prostaglandin / chemistry*
  • Receptors, Prostaglandin / genetics
  • Signal Transduction
  • Sulfonamides / chemistry

Substances

  • CAY 10471
  • Carbazoles
  • Indoleacetic Acids
  • Ligands
  • Pyridines
  • Receptors, G-Protein-Coupled
  • Receptors, Immunologic
  • Receptors, Prostaglandin
  • Sulfonamides
  • fevipiprant
  • Prostaglandin D2
  • prostaglandin D2 receptor