6D27

Crystal structure of the prostaglandin D2 receptor CRTH2 with CAY10471

Summary for 6D27

• Entry DOI: 10.2210/pdb6d27/pdb
• Related: 6D26
• Descriptor: Prostaglandin D2 receptor 2, Endolysin chimera, SULFATE ION, [(3R)-3-{[(4-fluorophenyl)sulfonyl](methyl)amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl]acetic acid, ... (9 entities in total)
• Functional Keywords: gpcr, membrane protein-antagonist complex, membrane protein/antagonist
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 54788.63

Authors

Wang, L.,Yao, D.,Deepak, K.,Liu, H.,Gong, W.,Fan, H.,Wei, Z.,Zhang, C. (deposition date: 2018-04-13, release date: 2018-10-03, Last modification date: 2023-10-04)

Primary citation

Wang, L.,Yao, D.,Deepak, R.N.V.K.,Liu, H.,Xiao, Q.,Fan, H.,Gong, W.,Wei, Z.,Zhang, C.
Structures of the Human PGD2Receptor CRTH2 Reveal Novel Mechanisms for Ligand Recognition.
Mol. Cell, 72:48-59.e4, 2018

PubMed Abstract: The signaling of prostaglandin D (PGD) 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, which differs significantly from the binding pose and binding environment of lysophospholipids and endocannabinoids, revealing a new mechanism for lipid recognition by GPCRs.

PubMed: 30220562
DOI: 10.1016/j.molcel.2018.08.009

Experimental method

X-RAY DIFFRACTION (2.738 Å)