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Structural basis for lysophosphatidylserine recognition by GPR34
Tamaki Izume1, Ryo Kawahara1, Akiharu Uwamizu2
1Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Nature Communications
|February 7, 2024
Summary
We determined the structure of GPR34 bound to ligands, revealing how it recognizes lysophosphatidylserine (LysoPS). This structural insight aids in developing new GPR34-targeted anticancer drugs.
Area of Science:
- Structural Biology
- Pharmacology
- Immunology
Background:
- GPR34 is a G-protein coupled receptor with immunomodulatory functions.
- It recognizes lysophosphatidylserine (LysoPS) as a potential ligand.
Purpose of the Study:
- To elucidate the structural basis of GPR34 ligand recognition.
- To provide insights for developing GPR34-targeting anticancer therapeutics.
Main Methods:
- Cryo-electron microscopy (cryo-EM) to determine the structure of human GPR34-Gi complex.
- Crystallography and molecular dynamics simulations.
- Biochemical and physiological experiments.
Main Results:
- Determined cryo-EM structures of human GPR34-Gi complex bound to LysoPS analogues.
- Identified a laterally open ligand-binding pocket allowing membrane-based agonist entry.
- Revealed specific interactions between GPR34 residues and the ligand's serine moiety and acyl chain.
- Confirmed 2-acyl LysoPS as the likely physiological ligand for GPR34.
Conclusions:
- The study provides high-resolution structures of GPR34 bound to its ligands.
- These structures illuminate the mechanism of LysoPS recognition by GPR34.
- The findings are crucial for the rational design of novel anticancer drugs targeting GPR34.
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