2. Academic Validation
  3. Conformational transitions and activation of the adhesion receptor CD97

Conformational transitions and activation of the adhesion receptor CD97

  • Mol Cell. 2024 Jan 9:S1097-2765(23)01039-0. doi: 10.1016/j.molcel.2023.12.020.
Chunyou Mao 1,  Ru-Jia Zhao 2,  Ying-Jun Dong 3,  Mingxin Gao 4,  Li-Nan Chen 5,  Chao Zhang 4,  Peng Xiao 2,  Jia Guo 5,  Jiao Qin 5,  Dan-Dan Shen 6,  Su-Yu Ji 3,  Shao-Kun Zang 3,  Huibing Zhang 5,  Wei-Wei Wang 7,  Qingya Shen 7,  Jin-Peng Sun 8,  Yan Zhang 9
Affiliations

Affiliations

  • 1 Center for Structural Pharmacology and Therapeutics Development, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China. Electronic address: maochunyou@zju.edu.cn.
  • 2 Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 3 Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 4 Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 5 Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China.
  • 6 Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.
  • 7 Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China.
  • 8 Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China. Electronic address: sunjinpeng@sdu.edu.cn.
  • 9 Center for Structural Pharmacology and Therapeutics Development, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China; Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China; MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: zhang_yan@zju.edu.cn.
PMID: 38215752 DOI: 10.1016/j.molcel.2023.12.020
Abstract

Adhesion G protein-coupled receptors (aGPCRs) are evolutionarily ancient receptors involved in a variety of physiological and pathophysiological processes. Modulators of aGPCR, particularly antagonists, hold therapeutic promise for diseases like Cancer and immune and neurological disorders. Hindered by the inactive state structural information, our understanding of antagonist development and aGPCR activation faces challenges. Here, we report the cryo-electron microscopy structures of human CD97, a prototypical aGPCR that plays crucial roles in immune system, in its inactive apo and G13-bound fully active states. Compared with Other family GPCRs, CD97 adopts a compact inactive conformation with a constrained ligand pocket. Activation induces significant conformational changes for both extracellular and intracellular sides, creating larger cavities for Stachel sequence binding and G13 engagement. Integrated with functional and metadynamics analyses, our study provides significant mechanistic insights into the activation and signaling of aGPCRs, paving the way for future drug discovery efforts.

Keywords

CD97; Cryo-EM; adhesion GPCR; conformational transition; inactive structure; tethered agonism.

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