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

doi:10.1073/pnas.2102813118

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

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9 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 language	English (US)
Article number	e2102813118
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	118
Issue number	32
DOIs	https://doi.org/10.1073/pnas.2102813118
State	Published - Aug 10 2021

Keywords

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

ASJC Scopus subject areas

General

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10.1073/pnas.2102813118

Cite this

Liu, H., Deepak, R. N. V. K., Shiriaeva, A., Gati, C., Batyuk, A., Hu, H., Weierstall, U., Liu, W., Wang, L., Cherezov, V., Fan, H., & Zhang, C. (2021). Molecular basis for lipid recognition by the prostaglandin D₂ receptor CRTH2. Proceedings of the National Academy of Sciences of the United States of America, 118(32), Article e2102813118. https://doi.org/10.1073/pnas.2102813118

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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.",

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

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AU - Liu, Heng

AU - Deepak, R. N.V.Krishna

AU - Shiriaeva, Anna

AU - Gati, Cornelius

AU - Batyuk, Alexander

AU - Hu, Hao

AU - Weierstall, Uwe

AU - Liu, Wei

AU - Wang, Lei

AU - Cherezov, Vadim

AU - Fan, Hao

AU - Zhang, Cheng

PY - 2021/8/10

Y1 - 2021/8/10

N2 - 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.

AB - 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.

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KW - Lipid binding

KW - MD simulations

KW - Prostaglandin D

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Molecular basis for lipid recognition by the prostaglandin D₂ receptor CRTH2

Abstract

Keywords

ASJC Scopus subject areas

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XFEL crystal structure of the prostaglandin D2 receptor CRTH2 in complex with 15R-methyl-PGD2

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Molecular basis for lipid recognition by the prostaglandin D2 receptor CRTH2

Abstract

Keywords

ASJC Scopus subject areas

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Datasets

XFEL crystal structure of the prostaglandin D2 receptor CRTH2 in complex with 15R-methyl-PGD2

Cite this

Molecular basis for lipid recognition by the prostaglandin D₂ receptor CRTH2