9IYB

Cryo-EM Structure of the Prostaglandin D2 Receptor 2-PGD2 Coupled to G Protein

This is a non-PDB format compatible entry.

Summary for 9IYB

• Entry DOI: 10.2210/pdb9iyb/pdb
• EMDB information: 60994
• Descriptor: Prostaglandin D2 receptor 2, Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (8 entities in total)
• Functional Keywords: gpcr, dp2, pgd2, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 157108.39

Authors

Xu, J.,Xu, Y.,Wu, C.,Xu, H.E. (deposition date: 2024-07-30, release date: 2024-12-04, Last modification date: 2025-02-26)

Primary citation

Xu, J.,Xu, Y.,Hou, L.,He, X.,Li, Y.,Zhao, J.,Meng, X.,Wang, J.J.,Wu, Y.,Zhang, H.,Li, Y.,Hu, W.,Yuan, Q.,Wu, K.,Cheng, X.,Jiang, Y.,Xia, Y.,Xu, H.E.,Wu, C.
Molecular basis of lipid and ligand regulation of prostaglandin receptor DP2.
Proc.Natl.Acad.Sci.USA, 121:e2403304121-e2403304121, 2024

PubMed Abstract: Prostaglandin D2 receptor 2 (DP2) is an important anti-inflammatory and antiallergic drug target. While inactive DP2 structures are known, its activation mechanisms and biased signaling remain unclear. Here, we report cryo-EM structures of an apo DP2-Gi complex, a DP2-Gi complex bound to the endogenous ligand Prostaglandin D (PGD), and a DP2-Gi complex bound to indomethacin, an arrestin-biased ligand, at resolutions of 2.5 Å, 2.8Å, and 2.3 Å, respectively. These structures reveal a distinct binding pose of PGD and indomethacin and provide key insights into receptor activation and transducer coupling. Combining the structural data with functional studies, we uncover the molecular basis for biased signaling of indomethacin toward β-arrestin over G proteins. Notably, a phospholipid binding site was identified at the DP2-G protein interface that modulates DP2-G protein interactions. Together, our functional and structural findings provide insights into DP2 activation, biased signaling, drug interactions, and lipid regulation, enabling rational design of safer antiallergy therapeutics targeting this key immune receptor.

PubMed: 39665758
DOI: 10.1073/pnas.2403304121

Experimental method

ELECTRON MICROSCOPY (2.82 Å)