TY - JOUR
T1 - Structural basis of lysophosphatidylserine receptor GPR174 ligand recognition and activation
AU - Liang, Jiale
AU - Inoue, Asuka
AU - Ikuta, Tatsuya
AU - Xia, Ruixue
AU - Wang, Na
AU - Kawakami, Kouki
AU - Xu, Zhenmei
AU - Qian, Yu
AU - Zhu, Xinyan
AU - Zhang, Anqi
AU - Guo, Changyou
AU - Huang, Zhiwei
AU - He, Yuanzheng
N1 - Funding Information:
We thank Kayo Sato, Shigeko Nakano, and Ayumi Inoue at Tohoku University for their assistance in plasmid preparation and cell-based GPCR assays. This work was supported by the National Natural Science Foundation of China (32070048 to Y.H.). A.I. was funded by the Japan Society for the Promotion of Science (JSPS) KAKENHI grants JP21H04791, JP21H05113, JPJSBP120213501, and JPJSBP120218801; FOREST Program JPMJFR215T and JST Moonshot Research and Development Program JPMJMS2023 from Japan Science and Technology Agency (JST); JP22ama121038 and JP22zf0127007 from Japan Agency for Medical Research and Development (AMED); The Uehara Memorial Foundation; and Daiichi Sankyo Foundation of Life Science. The MD simulation was carried out using the TSUBAME 3.0 supercomputer at the Tokyo Institute of Technology.
Funding Information:
We thank Kayo Sato, Shigeko Nakano, and Ayumi Inoue at Tohoku University for their assistance in plasmid preparation and cell-based GPCR assays. This work was supported by the National Natural Science Foundation of China (32070048 to Y.H.). A.I. was funded by the Japan Society for the Promotion of Science (JSPS) KAKENHI grants JP21H04791, JP21H05113, JPJSBP120213501, and JPJSBP120218801; FOREST Program JPMJFR215T and JST Moonshot Research and Development Program JPMJMS2023 from Japan Science and Technology Agency (JST); JP22ama121038 and JP22zf0127007 from Japan Agency for Medical Research and Development (AMED); The Uehara Memorial Foundation; and Daiichi Sankyo Foundation of Life Science. The MD simulation was carried out using the TSUBAME 3.0 supercomputer at the Tokyo Institute of Technology.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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 Gs 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 Gs 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.
AB - 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 Gs 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 Gs 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.
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U2 - 10.1038/s41467-023-36575-0
DO - 10.1038/s41467-023-36575-0
M3 - Article
C2 - 36823105
AN - SCOPUS:85148810599
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1012
ER -