7cz5

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

Structural highlights

7cz5 is a 6 chain structure with sequence from Bos taurus, Homo sapiens, Rattus norvegicus and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 2.6Å
Ligands:CLR, PLM
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

GHRHR_HUMAN Isolated growth hormone deficiency type IB. The disease is caused by mutations affecting the gene represented in this entry.[1] [2] [3]

Function

GHRHR_HUMAN Receptor for GRF, coupled to G proteins which activate adenylyl cyclase. Stimulates somatotroph cell growth, growth hormone gene transcription and growth hormone secretion.

Publication Abstract from PubMed

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 A. 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.

Structural basis for activation of the growth hormone-releasing hormone receptor.,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, Wang MW Nat Commun. 2020 Oct 15;11(1):5205. doi: 10.1038/s41467-020-18945-0. PMID:33060564[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. Salvatori R, Fan X, Phillips JA 3rd, Espigares-Martin R, Martin De Lara I, Freeman KL, Plotnick L, Al-Ashwal A, Levine MA. Three new mutations in the gene for the growth hormone (gh)-releasing hormone receptor in familial isolated gh deficiency type ib. J Clin Endocrinol Metab. 2001 Jan;86(1):273-9. PMID:11232012
  2. Salvatori R, Hayashida CY, Aguiar-Oliveira MH, Phillips JA 3rd, Souza AH, Gondo RG, Toledo SP, Conceicao MM, Prince M, Maheshwari HG, Baumann G, Levine MA. Familial dwarfism due to a novel mutation of the growth hormone-releasing hormone receptor gene. J Clin Endocrinol Metab. 1999 Mar;84(3):917-23. PMID:10084571 doi:http://dx.doi.org/10.1210/jcem.84.3.5599
  3. Carakushansky M, Whatmore AJ, Clayton PE, Shalet SM, Gleeson HK, Price DA, Levine MA, Salvatori R. A new missense mutation in the growth hormone-releasing hormone receptor gene in familial isolated GH deficiency. Eur J Endocrinol. 2003 Jan;148(1):25-30. PMID:12534354
  4. 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, Wang MW. Structural basis for activation of the growth hormone-releasing hormone receptor. Nat Commun. 2020 Oct 15;11(1):5205. PMID:33060564 doi:10.1038/s41467-020-18945-0

Contents


PDB ID 7cz5

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