Cryo-EM Structure of human HCN3 channel and its regulation by cAMP

Bo Yu; Qiuyuan Lu; Jian Li; Xinyu Cheng; Han Hu; Yuanshuo Li; Tong Che; Yaoguang Hua; Haihai Jiang; Yuting Zhang; Cuiling Xian; Tingting Yang; Ying Fu; Yixiang Chen; Weiwei Nan; Peter J McCormick; Bing Xiong; Jingjing Duan; Bo Zeng; Yanyan Li; Yang Fu; Jin Zhang

doi:10.1016/j.jbc.2024.107288

Cryo-EM Structure of human HCN3 channel and its regulation by cAMP

J Biol Chem. 2024 Apr 16:107288. doi: 10.1016/j.jbc.2024.107288. Online ahead of print.

Authors

Bo Yu¹, Qiuyuan Lu², Jian Li³, Xinyu Cheng¹, Han Hu⁴, Yuanshuo Li⁴, Tong Che¹, Yaoguang Hua¹, Haihai Jiang¹, Yuting Zhang⁴, Cuiling Xian⁴, Tingting Yang¹, Ying Fu¹, Yixiang Chen¹, Weiwei Nan¹, Peter J McCormick⁵, Bing Xiong⁶, Jingjing Duan⁷, Bo Zeng⁸, Yanyan Li⁹, Yang Fu², Jin Zhang¹

Affiliations

¹ The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China; The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
² School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China 518055.
³ College of Pharmacy, Gannan Medical University, Ganzhou 341000, China.
⁴ Shenzhen Crystalo Biopharmaceutical Co., Ltd, Shenzhen, Guangdong, 518118, China.
⁵ William Harvey Research Institute, Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁶ Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuchongzhiRoad , Shanghai 201203, China.
⁷ Human Aging Research Institute (HARI), School of Life Sciences, Nanchang University, Nanchang, Jiangxi, 330031, China.
⁸ Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan 646000, China.
⁹ Department of Chemical Biology, School of Life Southern University of Science and Technology, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China; Institute for Biological Electron Microscopy, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China.

PMID: 38636662
DOI: 10.1016/j.jbc.2024.107288

Abstract

HCN channels are important for regulating heart rhythm and nerve activity and have been studied as potential drug targets for treating depression, arrhythmia, nerve pain and epilepsy.Despite possessing unique pharmacological properties, HCN channels share common characteristics in that they are activated by hyperpolarization and modulated by cAMP and other membrane lipids. However, the mechanisms of how these ligands bind and modulate HCN channels are unclear. In this study, we solved structures of full-length human HCN3 using cryo-EM and captured two different states, including a state without any ligand bound and a state with cAMP bound. Our structures reveal the novel binding sites for cholesteryl hemisuccinate in apo-state and show how cholesteryl hemisuccinate and cAMP binding cause conformational changes in different states. These findings explain how these small modulators are sensed in mammals at the molecular level.The results of our study could help design more potent and specific compounds to influence HCN channel activity and offer new therapeutic possibilities for diseases that lack effective treatment.