Molecular basis for lipid recognition by the prostaglandin D2 receptor CRTH2

Heng Liu, R. N.V.Krishna Deepak, Anna Shiriaeva, Cornelius Gati, Alexander Batyuk, Hao Hu, Uwe Weierstall, Wei Liu, Lei Wang, Vadim Cherezov, Hao Fan, Cheng Zhang

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere2102813118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number32
DOIs
StatePublished - Aug 10 2021

Keywords

  • CRTH2 (DP2)
  • Crystal structure
  • Lipid binding
  • MD simulations
  • Prostaglandin D

ASJC Scopus subject areas

  • General

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