期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2102813118
关键词
CRTH2 (DP2); prostaglandin D-2; lipid binding; crystal structure; MD simulations
资金
- Biomedical Research Council, A*STAR
- Science and Technology Center Program of the NSF through BioXFEL [1231306]
- US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
- National Institute of General Medical Sciences, NIH of the United States [R35GM128641]
This study elucidated the crystal structure of human CRTH2 bound to a PGD(2) derivative, revealing different binding modes between 15mPGD(2) and PGE(2). The research also highlighted the critical roles of charged residues in lipid recognition by GPCRs, suggesting potential implications for lipid GPCR studies.
Prostaglandin D-2 (PGD(2)) 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 PGD(2) derivative, 15R-methyl-PGD(2) (15mPGD(2)), by serial femtosecond crystallography. The structure revealed a polar group in-binding mode of 15mPGD(2) contrasting the polar group out-binding mode of PGE(2) 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.
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