7CZ5

Cryo-EM structure of the human growth hormone-releasing hormone receptor-Gs protein complex

Summary for 7CZ5

• Entry DOI: 10.2210/pdb7cz5/pdb
• EMDB information: 30505
• Descriptor: Growth hormone-releasing hormone receptor,growth hormone-releasing hormone receptor, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Somatoliberin, ... (9 entities in total)
• Functional Keywords: cognate receptor, class b g-protein-coupled receptors, single particle, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 178562.25

Authors

Zhou, F.,Zhang, H.,Cong, Z.,Zhao, L.,Zhou, Q.,Mao, C.,Cheng, X.,Shen, D.,Cai, X.,Ma, C.,Wang, Y.,Dai, A.,Zhou, Y.,Sun, W.,Zhao, F.,Zhao, S.,Jiang, H.,Jiang, Y.,Yang, D.,Xu, H.E.,Zhang, Y.,Wang, M. (deposition date: 2020-09-07, release date: 2020-11-18, Last modification date: 2025-06-25)

Primary citation

Zhou, F.,Zhang, H.,Cong, Z.,Zhao, L.H.,Zhou, Q.,Mao, C.,Cheng, X.,Shen, D.D.,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.,Wang, M.W.
Structural basis for activation of the growth hormone-releasing hormone receptor.
Nat Commun, 11:5205-5205, 2020

PubMed 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.

PubMed: 33060564
DOI: 10.1038/s41467-020-18945-0

Experimental method

ELECTRON MICROSCOPY (2.6 Å)