Structures of the human PGD2 receptor CRTH2 reveal novel mechanisms for ligand recognition

Structures of the human PGD2 receptor CRTH2 reveal novel mechanisms for ligand recognition
Title:
Structures of the human PGD2 receptor CRTH2 reveal novel mechanisms for ligand recognition
Other Titles:
Molecular Cell
Publication Date:
13 September 2018
Citation:
Structures of the Human PGD2 Receptor CRTH2 Reveal Novel Mechanisms for Ligand Recognition Wang, Lei et al. Molecular Cell, Volume 72, Issue 1, 48 - 59.e4
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.
License type:
PublisherCopyrights
Funding Info:
We acknowledge the financial support from the University of Pittsburgh , the NIH (Maximizing Investigators’ Research Award [MIRA] R351R35GM128641 to C.Z.), the Biomedical Research Council ( A∗STAR to R.N.V.K.D. and H.F.), and the National Natural Science Foundation of China ( 31770791 and 315707410 to Z.W.). Z.W. is also supported by the startup funds from Southern University of Science and Technology and the Recruitment Program of Global Youth Experts of China .
Description:
The full paper can be downloaded from the publisher's URL here: https://doi.org/10.1016/j.molcel.2018.08.009
ISSN:
1097-2765
1097-4164
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