Structural basis of lysophosphatidylserine receptor GPR174 ligand recognition and activation

Jiale Liang; Asuka Inoue; Tatsuya Ikuta; Ruixue Xia; Na Wang; Kouki Kawakami; Zhenmei Xu; Yu Qian; Xinyan Zhu; Anqi Zhang; Changyou Guo; Zhiwei Huang; Yuanzheng He

doi:10.1038/s41467-023-36575-0

Structural basis of lysophosphatidylserine receptor GPR174 ligand recognition and activation

Nat Commun. 2023 Feb 23;14(1):1012. doi: 10.1038/s41467-023-36575-0.

Authors

Jiale Liang^#¹, Asuka Inoue^#², Tatsuya Ikuta³, Ruixue Xia¹, Na Wang¹, Kouki Kawakami³, Zhenmei Xu¹, Yu Qian¹, Xinyan Zhu¹, Anqi Zhang⁴, Changyou Guo⁴, Zhiwei Huang⁴, Yuanzheng He⁵

Affiliations

¹ Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, 150001, Harbin, China.
² Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, 980-8578, Miyagi, Japan. iaska@tohoku.ac.jp.
³ Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, 980-8578, Miyagi, Japan.
⁴ HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
⁵ Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, 150001, Harbin, China. ajian.he@hit.edu.cn.

^# Contributed equally.

Abstract

Lysophosphatidylserine (LysoPS) is a lipid mediator that induces multiple cellular responses through binding to GPR174. Here, we present the cryo-electron microscopy (cryo-EM) structure of LysoPS-bound human GPR174 in complex with G_s protein. The structure reveals a ligand recognition mode, including the negatively charged head group of LysoPS forms extensive polar interactions with surrounding key residues of the ligand binding pocket, and the L-serine moiety buries deeply into a positive charged cavity in the pocket. In addition, the structure unveils a partially open pocket on transmembrane domain helix (TM) 4 and 5 for a lateral entry of ligand. Finally, the structure reveals a G_s engaging mode featured by a deep insertion of a helix 5 (αH5) and extensive polar interactions between receptor and αH5. Taken together, the information revealed by our structural study provides a framework for understanding LysoPS signaling and a rational basis for designing LysoPS receptor-targeting drugs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cryoelectron Microscopy
Humans
Ligands
Receptors, G-Protein-Coupled* / metabolism
Signal Transduction*

Substances

Receptors, G-Protein-Coupled
lysophosphatidylserine
Ligands
GPR174 protein, human