9WXM

Cryo-EM structure of the full-length GPR15L bound GPR15-Gi complex

Summary for 9WXM

• Entry DOI: 10.2210/pdb9wxm/pdb
• EMDB information: 66350
• Descriptor: Protein GPR15LG, G-protein coupled receptor 15, Guanine nucleotide-binding protein G(i) subunit alpha-3, ... (6 entities in total)
• Functional Keywords: gpcr, gpr15l, gpr15, membrane protein/immune system, membrane protein-immune system complex
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 165122.26

Authors

Han, S.,Wu, B.,Zhao, Q. (deposition date: 2025-09-25, release date: 2025-11-19, Last modification date: 2025-12-17)

Primary citation

Chen, S.,Han, X.,Zhang, Y.,Ma, L.,Yi, C.,Chu, X.,Tan, Q.,Han, S.,Zhao, Q.,Wu, B.
Molecular insights into ligand recognition and receptor activation of GPR15.
Iscience, 28:113935-113935, 2025

PubMed Abstract: In response to the chemokine-like peptide GPR15L, G protein-coupled receptor 15 (GPR15) is crucial for immune cell trafficking and inflammatory diseases. However, understanding of its physiology and pathology is hindered by lack of molecular details of the interaction between GPR15 and the full-length GPR15L. Here, we report the structure of GPR15 bound to the full-length GPR15L and G protein. Combined with mutagenesis data, this structure reveals key interactions that define ligand recognition and a subpocket that governs GPR15L selectivity and receptor activation. Molecular dynamics simulations suggest that sulfation modifications in the N-terminal region of GPR15 may play a role in stabilizing the binding between GPR15 and the core region of GPR15L. Furthermore, molecular docking of some potential small-molecule antagonists suggests a conserved molecular pattern of these ligands inhibiting receptor activation. These findings provide essential insight into functional modulation of GPR15 and would facilitate development of therapeutic strategies for treatment of inflammation and immune diseases.

PubMed: 41321630
DOI: 10.1016/j.isci.2025.113935

Experimental method

ELECTRON MICROSCOPY (3.3 Å)