期刊
NATURE COMMUNICATIONS
卷 11, 期 1, 页码 -出版社
NATURE RESEARCH
DOI: 10.1038/s41467-020-18945-0
关键词
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资金
- National Natural Science Foundation of China [81872915, 81922071, 81773792, 81973373, 21704064, 31770796, 31971178]
- National Science and Technology Major Project of ChinaKey New Drug Creation and Manufacturing Program [2018ZX09735-001, 2018ZX09711002-002-005, 2018ZX09711002-002-002]
- Shanghai Municipal Science and Technology Major Project [2019SHZDZX02]
- Ministry of Science and Technology of China [XDB08020303]
- National Key R&D Program of China [2018YFA0507000]
- Zhejiang Province Science Fund for Distinguished Young Scholars [LR19H310001]
- Shanghai Science and Technology Development Fund [18ZR1447800]
- Young Innovator Association of CAS [2018325]
- SA-SIBS Scholarship Program
- Novo Nordisk-CAS Research Fund [NNCAS-2017-1-CC]
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 angstrom. This high-resolution structure reveals a characteristic hormone recognition pattern of GHRH by GHRHR, where the alpha-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.
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