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==== | ==Cryo-EM structure of the human growth hormone-releasing hormone receptor-Gs protein complex== | ||
<StructureSection load='7cz5' size='340' side='right'caption='[[7cz5]]' scene=''> | <StructureSection load='7cz5' size='340' side='right'caption='[[7cz5]], [[Resolution|resolution]] 2.60Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[7cz5]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens], [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7CZ5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7CZ5 FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.6Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=PLM:PALMITIC+ACID'>PLM</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7cz5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7cz5 OCA], [https://pdbe.org/7cz5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7cz5 RCSB], [https://www.ebi.ac.uk/pdbsum/7cz5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7cz5 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | |||
[https://www.uniprot.org/uniprot/GHRHR_HUMAN GHRHR_HUMAN] Isolated growth hormone deficiency type IB. The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:11232012</ref> <ref>PMID:10084571</ref> <ref>PMID:12534354</ref> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/GHRHR_HUMAN 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. | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:33060564</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7cz5" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Transducin 3D structures|Transducin 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Bos taurus]] | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Z | [[Category: Rattus norvegicus]] | ||
[[Category: Synthetic construct]] | |||
[[Category: Cai X]] | |||
[[Category: Cheng X]] | |||
[[Category: Cong Z]] | |||
[[Category: Dai A]] | |||
[[Category: Jiang H]] | |||
[[Category: Jiang Y]] | |||
[[Category: Ma C]] | |||
[[Category: Mao C]] | |||
[[Category: Shen D]] | |||
[[Category: Sun W]] | |||
[[Category: Wang M]] | |||
[[Category: Wang Y]] | |||
[[Category: Xu HE]] | |||
[[Category: Yang D]] | |||
[[Category: Zhang H]] | |||
[[Category: Zhang Y]] | |||
[[Category: Zhao F]] | |||
[[Category: Zhao L]] | |||
[[Category: Zhao S]] | |||
[[Category: Zhou F]] | |||
[[Category: Zhou Q]] | |||
[[Category: Zhou Y]] | |||
Latest revision as of 09:11, 21 November 2024
Cryo-EM structure of the human growth hormone-releasing hormone receptor-Gs protein complexCryo-EM structure of the human growth hormone-releasing hormone receptor-Gs protein complex
Structural highlights
DiseaseGHRHR_HUMAN Isolated growth hormone deficiency type IB. The disease is caused by mutations affecting the gene represented in this entry.[1] [2] [3] FunctionGHRHR_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 PubMedGrowth 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. See AlsoReferences
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