Structural basis for activation of the growth hormone-releasing hormone receptor

Fulai Zhou, Huibing Zhang, Zhaotong Cong, Li-Hua Zhao, Qingtong Zhou, Chunyou Mao, Xi Cheng, Dan-Dan Shen, Xiaoqing Cai, Cheng Ma, Yuzhe Wang, Antao Dai, Yan Zhou, Wen Sun, Fenghui Zhao, Suwen Zhao, Hualiang Jiang, Yi Jiang, Dehua Yang (), H. Eric Xu (), Yan Zhang () and Ming-Wei Wang ()
Additional contact information
Fulai Zhou: Chinese Academy of Sciences
Huibing Zhang: Zhejiang University School of Medicine
Zhaotong Cong: Fudan University
Li-Hua Zhao: Chinese Academy of Sciences
Qingtong Zhou: ShanghaiTech University
Chunyou Mao: Zhejiang University School of Medicine
Xi Cheng: Chinese Academy of Sciences
Dan-Dan Shen: Zhejiang University School of Medicine
Xiaoqing Cai: Chinese Academy of Sciences
Cheng Ma: Zhejiang University School of Medicine
Yuzhe Wang: Chinese Academy of Sciences
Antao Dai: Chinese Academy of Sciences
Yan Zhou: Chinese Academy of Sciences
Wen Sun: Chinese Academy of Sciences
Fenghui Zhao: Fudan University
Suwen Zhao: ShanghaiTech University
Hualiang Jiang: Chinese Academy of Sciences
Yi Jiang: Chinese Academy of Sciences
Dehua Yang: Chinese Academy of Sciences
H. Eric Xu: Chinese Academy of Sciences
Yan Zhang: Zhejiang University School of Medicine
Ming-Wei Wang: Chinese Academy of Sciences

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: Abstract Growth hormone-releasing hormone (GHRH) regulates the secretion of growth hormone that virtually controls metabolism and growth of every tissue through its binding to the cognate receptor (GHRHR). Malfunction in GHRHR signaling is associated with abnormal growth, making GHRHR an attractive therapeutic target against dwarfism (e.g., isolated growth hormone deficiency, IGHD), gigantism, lipodystrophy and certain cancers. Here, we report the cryo-electron microscopy (cryo-EM) structure of the human GHRHR bound to its endogenous ligand and the stimulatory G protein at 2.6 Å. This high-resolution structure reveals a characteristic hormone recognition pattern of GHRH by GHRHR, where the α-helical GHRH forms an extensive and continuous network of interactions involving all the extracellular loops (ECLs), all the transmembrane (TM) helices except TM4, and the extracellular domain (ECD) of GHRHR, especially the N-terminus of GHRH that engages a broad set of specific interactions with the receptor. Mutagenesis and molecular dynamics (MD) simulations uncover detailed mechanisms by which IGHD-causing mutations lead to the impairment of GHRHR function. Our findings provide insights into the molecular basis of peptide recognition and receptor activation, thereby facilitating the development of structure-based drug discovery and precision medicine.

Date: 2020
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DOI: 10.1038/s41467-020-18945-0

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