1. Structural basis for activation of the growth hormone-releasing hormone receptor.
- Author
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Zhou F, Zhang H, Cong Z, Zhao LH, Zhou Q, Mao C, Cheng X, Shen DD, Cai X, Ma C, Wang Y, Dai A, Zhou Y, Sun W, Zhao F, Zhao S, Jiang H, Jiang Y, Yang D, Eric Xu H, Zhang Y, and Wang MW
- Subjects
- Binding Sites, Cryoelectron Microscopy, Dwarfism, Pituitary genetics, GTP-Binding Proteins, Growth Hormone-Releasing Hormone deficiency, Humans, Molecular Dynamics Simulation, Mutagenesis, Mutation, Protein Conformation, Protein Conformation, alpha-Helical, Receptors, Neuropeptide genetics, Receptors, Pituitary Hormone-Regulating Hormone genetics, Signal Transduction, Growth Hormone-Releasing Hormone chemistry, Growth Hormone-Releasing Hormone metabolism, Receptors, Neuropeptide chemistry, Receptors, Neuropeptide metabolism, Receptors, Pituitary Hormone-Regulating Hormone chemistry, Receptors, Pituitary Hormone-Regulating Hormone metabolism
- 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.
- Published
- 2020
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