2. Academic Validation
  3. Cryo-EM structures of human GPR34 enable the identification of selective antagonists

Cryo-EM structures of human GPR34 enable the identification of selective antagonists

  • Proc Natl Acad Sci U S A. 2023 Sep 26;120(39):e2308435120. doi: 10.1073/pnas.2308435120.
Anjie Xia # 1 2,  Xihao Yong # 1,  Changbin Zhang # 1,  Guifeng Lin # 1,  Guowen Jia # 1,  Chang Zhao # 1,  Xin Wang # 1,  Yize Hao # 3 4,  Yifei Wang 1,  Pei Zhou 5,  Xin Yang 1,  Yue Deng 1,  Chao Wu 1,  Yujiao Chen 1,  Jiawei Zhu 1,  Xiaodi Tang 1,  Jingming Liu 1,  Shiyu Zhang 1,  Jiahao Zhang 1,  Zheng Xu 1,  Qian Hu 1,  Jinlong Zhao 1,  Yuting Yue 3 4,  Wei Yan 1,  Zhaoming Su 1,  Yuquan Wei 1,  Rongbin Zhou 3 4,  Haohao Dong 1,  Zhenhua Shao 1 6,  Shengyong Yang 1 6
Affiliations

Affiliations

  • 1 Department of Biotherapy, Cancer Center and Kidney Research Institute, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 2 Department of Ophthalmology and Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 3 The Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230027, China.
  • 4 Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, Anhui 230601, China.
  • 5 Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China.
  • 6 Frontier Medical Center Tianfu Jincheng Laboratory, Chengdu, Sichuan 610212, China.
  • # Contributed equally.
PMID: 37733739 DOI: 10.1073/pnas.2308435120
Abstract

GPR34 is a functional G-protein-coupled receptor of Lysophosphatidylserine (LysoPS), and has pathogenic roles in numerous diseases, yet remains poorly targeted. We herein report a cryo-electron microscopy (cryo-EM) structure of GPR34 bound with LysoPS (18:1) and Gi protein, revealing a unique ligand recognition mode with the negatively charged head group of LysoPS occupying a polar cavity formed by TM3, 6 and 7, and the hydrophobic tail of LysoPS residing in a lateral open hydrophobic groove formed by TM3-5. Virtual screening and subsequent structural optimization led to the identification of a highly potent and selective antagonist (YL-365). Design of fusion proteins allowed successful determination of the challenging cryo-EM structure of the inactive GPR34 complexed with YL-365, which revealed the competitive binding of YL-365 in a portion of the orthosteric binding pocket of GPR34 and the antagonist-binding-induced allostery in the receptor, implicating the inhibition mechanism of YL-365. Moreover, YL-365 displayed excellent activity in a neuropathic pain model without obvious toxicity. Collectively, this study offers mechanistic insights into the endogenous agonist recognition and antagonist inhibition of GPR34, and provides proof of concept that targeting GPR34 represents a promising strategy for disease treatment.

Keywords

GPCR; GPR34; antagonist; cryo-EM.

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  • HY-156815
    99.96%, GPR34拮抗剂
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