Molecular basis for lipid recognition by the prostaglandin D2 receptor CRTH2. Proc Natl Acad Sci U S A 2021 Aug 10;118(32)
Date
08/04/2021Pubmed ID
34341104Pubmed Central ID
PMC8364189DOI
10.1073/pnas.2102813118Scopus ID
2-s2.0-85111810793 (requires institutional sign-in at Scopus site) 10 CitationsAbstract
Prostaglandin D2 (PGD2) signals through the G protein-coupled receptor (GPCR) CRTH2 to mediate various inflammatory responses. CRTH2 is the only member of the prostanoid receptor family that is phylogenetically distant from others, implying a nonconserved mechanism of lipid action on CRTH2. Here, we report a crystal structure of human CRTH2 bound to a PGD2 derivative, 15R-methyl-PGD2 (15mPGD2), by serial femtosecond crystallography. The structure revealed a "polar group in"-binding mode of 15mPGD2 contrasting the "polar group out"-binding mode of PGE2 in its receptor EP3. Structural comparison analysis suggested that these two lipid-binding modes, associated with distinct charge distributions of ligand-binding pockets, may apply to other lipid GPCRs. Molecular dynamics simulations together with mutagenesis studies also identified charged residues at the ligand entry port that function to capture lipid ligands of CRTH2 from the lipid bilayer. Together, our studies suggest critical roles of charge environment in lipid recognition by GPCRs.
Author List
Liu H, Deepak RNVK, Shiriaeva A, Gati C, Batyuk A, Hu H, Weierstall U, Liu W, Wang L, Cherezov V, Fan H, Zhang CAuthor
Wei Liu PhD Associate Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Crystallography, X-RayHumans
Lipid Metabolism
Molecular Dynamics Simulation
Mutation
Prostaglandin D2
Protein Conformation
Receptors, Immunologic
Receptors, Prostaglandin