Structures of G-protein coupled receptor HCAR3 in complex with selective agonists reveal the basis for ligand recognition and selectivity

Fang Ye; Zhiyi Zhang; Binghao Zhang; Xinyu Li; Jiaxi Deng; Qian Miao; Peiruo Ning; Yunlin Chi; Geng Chen; Zhangsong Wu; Qian Wang; Lezhi Xu; Ningjie Gong; Bangning Cheng; Zhigang Ma; Chungen Qian; Lizhe Zhu; Xin Pan; Yang Du

doi:10.1371/journal.pbio.3003480

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Structures of G-protein coupled receptor HCAR3 in complex with selective agonists reveal the basis for ligand recognition and selectivity

Fang Ye ,

Contributed equally to this work with: Fang Ye, Zhiyi Zhang, Binghao Zhang, Xinyu Li

Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing – original draft, Writing – review & editing

¶☯ These authors contributed equally to this work.

Affiliations Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning, China, Kobilka Institute of Innovative Drug Discovery, The Second Affiliated Hospital, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, Chinese University of Hong Kong, Shenzhen, Guangdong, China
⨯
Zhiyi Zhang ,

Contributed equally to this work with: Fang Ye, Zhiyi Zhang, Binghao Zhang, Xinyu Li

Roles Data curation, Formal analysis, Investigation, Methodology, Software, Writing – original draft

¶☯ These authors contributed equally to this work.

Affiliations Kobilka Institute of Innovative Drug Discovery, The Second Affiliated Hospital, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, Chinese University of Hong Kong, Shenzhen, Guangdong, China, The Huanan Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, Guangdong, China
⨯
Binghao Zhang ,

Contributed equally to this work with: Fang Ye, Zhiyi Zhang, Binghao Zhang, Xinyu Li

Roles Data curation, Formal analysis, Investigation, Methodology, Project administration, Software, Validation, Visualization, Writing – original draft, Writing – review & editing

¶☯ These authors contributed equally to this work.

Affiliation Kobilka Institute of Innovative Drug Discovery, The Second Affiliated Hospital, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, Chinese University of Hong Kong, Shenzhen, Guangdong, China
⨯
Xinyu Li ,

Contributed equally to this work with: Fang Ye, Zhiyi Zhang, Binghao Zhang, Xinyu Li

Roles Data curation, Formal analysis, Investigation, Methodology, Project administration, Software, Writing – original draft

¶☯ These authors contributed equally to this work.

Affiliation Warshel Institute for Computational Biology, School of Medicine, the Chinese University of Hong Kong, Shenzhen, Guangdong, China
⨯
Jiaxi Deng,

Roles Formal analysis, Investigation

Affiliation Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning, China
⨯
Qian Miao,

Roles Formal analysis, Investigation

Affiliation Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning, China
⨯
Peiruo Ning,

Roles Formal analysis, Investigation

Affiliation Kobilka Institute of Innovative Drug Discovery, The Second Affiliated Hospital, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, Chinese University of Hong Kong, Shenzhen, Guangdong, China
⨯
Yunlin Chi,

Roles Formal analysis, Investigation

Affiliation Kobilka Institute of Innovative Drug Discovery, The Second Affiliated Hospital, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, Chinese University of Hong Kong, Shenzhen, Guangdong, China
⨯
Geng Chen,

Roles Formal analysis, Investigation

Affiliation Kobilka Institute of Innovative Drug Discovery, The Second Affiliated Hospital, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, Chinese University of Hong Kong, Shenzhen, Guangdong, China
⨯
Zhangsong Wu,

Roles Formal analysis, Investigation

Affiliation Kobilka Institute of Innovative Drug Discovery, The Second Affiliated Hospital, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, Chinese University of Hong Kong, Shenzhen, Guangdong, China
⨯
Qian Wang,

Roles Formal analysis, Investigation

Affiliation Kobilka Institute of Innovative Drug Discovery, The Second Affiliated Hospital, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, Chinese University of Hong Kong, Shenzhen, Guangdong, China
⨯
Lezhi Xu,

Roles Formal analysis, Investigation

Affiliation Kobilka Institute of Innovative Drug Discovery, The Second Affiliated Hospital, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, Chinese University of Hong Kong, Shenzhen, Guangdong, China
⨯
Ningjie Gong,

Roles Formal analysis, Investigation

Affiliation Kobilka Institute of Innovative Drug Discovery, The Second Affiliated Hospital, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, Chinese University of Hong Kong, Shenzhen, Guangdong, China
⨯
Bangning Cheng,

Roles Formal analysis, Investigation

Affiliation Warshel Institute for Computational Biology, School of Medicine, the Chinese University of Hong Kong, Shenzhen, Guangdong, China
⨯
Zhigang Ma ,

Roles Funding acquisition, Supervision, Writing – review & editing

* E-mail: qmc89@163.com (ZM); chungen_qian@hust.edu.cn (CQ); zhulizhe@cuhk.edu.cn (LZ); xinpanphd@163.com (XP); yangdu@cuhk.edu.cn (YD)

Affiliation Kobilka Institute of Innovative Drug Discovery, The Second Affiliated Hospital, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, Chinese University of Hong Kong, Shenzhen, Guangdong, China
⨯
Chungen Qian ,

Roles Supervision

* E-mail: qmc89@163.com (ZM); chungen_qian@hust.edu.cn (CQ); zhulizhe@cuhk.edu.cn (LZ); xinpanphd@163.com (XP); yangdu@cuhk.edu.cn (YD)

Affiliation Department of Reagent Research and Development, Shenzhen YHLO Biotech Co., Ltd., Shenzhen, Guangdong, China
⨯
Lizhe Zhu ,

Roles Supervision

* E-mail: qmc89@163.com (ZM); chungen_qian@hust.edu.cn (CQ); zhulizhe@cuhk.edu.cn (LZ); xinpanphd@163.com (XP); yangdu@cuhk.edu.cn (YD)

Affiliation Warshel Institute for Computational Biology, School of Medicine, the Chinese University of Hong Kong, Shenzhen, Guangdong, China
⨯
Xin Pan ,

Roles Formal analysis, Supervision, Writing – original draft

* E-mail: qmc89@163.com (ZM); chungen_qian@hust.edu.cn (CQ); zhulizhe@cuhk.edu.cn (LZ); xinpanphd@163.com (XP); yangdu@cuhk.edu.cn (YD)

Affiliation Department of Cardiology, Central Laboratory, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, China
⨯
[ ... ],
Yang Du

Roles Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

* E-mail: qmc89@163.com (ZM); chungen_qian@hust.edu.cn (CQ); zhulizhe@cuhk.edu.cn (LZ); xinpanphd@163.com (XP); yangdu@cuhk.edu.cn (YD)

Affiliation Kobilka Institute of Innovative Drug Discovery, The Second Affiliated Hospital, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, Chinese University of Hong Kong, Shenzhen, Guangdong, China

https://orcid.org/0000-0001-5115-0736

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Structures of G-protein coupled receptor HCAR3 in complex with selective agonists reveal the basis for ligand recognition and selectivity

Fang Ye,
Zhiyi Zhang,
Binghao Zhang,
Xinyu Li,
Jiaxi Deng,
Qian Miao,
Peiruo Ning,
Yunlin Chi,
Geng Chen,
Zhangsong Wu

Published: December 8, 2025
https://doi.org/10.1371/journal.pbio.3003480

About the Authors

Fang Ye

Contributed equally to this work with: Fang Ye, Zhiyi Zhang, Binghao Zhang, Xinyu Li

Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing – original draft, Writing – review & editing

¶☯ These authors contributed equally to this work.

Affiliations Guangxi Key Laboratory of Special Biomedicine, School of Medicine, Guangxi University, Nanning, China, Kobilka Institute of Innovative Drug Discovery, The Second Affiliated Hospital, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, Chinese University of Hong Kong, Shenzhen, Guangdong, China

Zhiyi Zhang

Contributed equally to this work with: Fang Ye, Zhiyi Zhang, Binghao Zhang, Xinyu Li

Roles Data curation, Formal analysis, Investigation, Methodology, Software, Writing – original draft

¶☯ These authors contributed equally to this work.

Affiliations Kobilka Institute of Innovative Drug Discovery, The Second Affiliated Hospital, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, Chinese University of Hong Kong, Shenzhen, Guangdong, China, The Huanan Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, Guangdong, China

Binghao Zhang

Contributed equally to this work with: Fang Ye, Zhiyi Zhang, Binghao Zhang, Xinyu Li

Roles Data curation, Formal analysis, Investigation, Methodology, Project administration, Software, Validation, Visualization, Writing – original draft, Writing – review & editing

¶☯ These authors contributed equally to this work.

Affiliation Kobilka Institute of Innovative Drug Discovery, The Second Affiliated Hospital, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, Chinese University of Hong Kong, Shenzhen, Guangdong, China

Xinyu Li

Contributed equally to this work with: Fang Ye, Zhiyi Zhang, Binghao Zhang, Xinyu Li

Roles Data curation, Formal analysis, Investigation, Methodology, Project administration, Software, Writing – original draft

¶☯ These authors contributed equally to this work.

Affiliation Warshel Institute for Computational Biology, School of Medicine, the Chinese University of Hong Kong, Shenzhen, Guangdong, China

Jiaxi Deng