2. Academic Validation
  3. A method for structure determination of GPCRs in various states

A method for structure determination of GPCRs in various states

  • Nat Chem Biol. 2023 Aug 14. doi: 10.1038/s41589-023-01389-0.
Qiong Guo # 1,  Binbin He # 1,  Yixuan Zhong # 1,  Haizhan Jiao # 2,  Yinhang Ren 3,  Qinggong Wang 1,  Qiangqiang Ge 1,  Yongxiang Gao 1,  Xiangyu Liu 3,  Yang Du 2,  Hongli Hu 4,  Yuyong Tao 5
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine, The First Affiliated Hospital of USTC, MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, Hefei National Center for Cross-Disciplinary Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 2 Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, China.
  • 3 Beijing Frontier Research Center for Biological Structure, Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Center for Life Sciences, School of Pharmaceutical Sciences, Tsinghua University, Beijing, China.
  • 4 Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen, China. [email protected].
  • 5 Department of Laboratory Medicine, The First Affiliated Hospital of USTC, MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, Hefei National Center for Cross-Disciplinary Sciences, Biomedical Sciences and Health Laboratory of Anhui Province, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. [email protected].
  • # Contributed equally.
PMID: 37580554 DOI: 10.1038/s41589-023-01389-0
Abstract

G-protein-coupled receptors (GPCRs) are a class of integral membrane proteins that detect environmental cues and trigger cellular responses. Deciphering the functional states of GPCRs induced by various ligands has been one of the primary goals in the field. Here we developed an effective universal method for GPCR cryo-electron microscopy structure determination without the need to prepare GPCR-signaling protein complexes. Using this method, we successfully solved the structures of the β2-adrenergic receptor (β2AR) bound to antagonistic and agonistic ligands and the adhesion GPCR ADGRL3 in the apo state. For β2AR, an intermediate state stabilized by the partial agonist was captured. For ADGRL3, the structure revealed that inactive ADGRL3 adopts a compact fold and that large unusual conformational changes on both the extracellular and intracellular sides are required for activation of Adhesion GPCRs. We anticipate that this method will open a new avenue for understanding GPCR structure‒function relationships and drug development.

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