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- PDB-7cz5: Cryo-EM structure of the human growth hormone-releasing hormone r... -

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Entry
Database: PDB / ID: 7cz5
TitleCryo-EM structure of the human growth hormone-releasing hormone receptor-Gs protein complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Growth hormone-releasing hormone receptor,growth hormone-releasing hormone receptor
  • Nanobody35
  • Somatoliberin
KeywordsMEMBRANE PROTEIN / cognate receptor / Class B G-protein-coupled receptors / single particle
Function / homology
Function and homology information


positive regulation of circadian sleep/wake cycle, REM sleep / regulation of intracellular steroid hormone receptor signaling pathway / growth hormone-releasing hormone receptor binding / growth hormone-releasing hormone receptor activity / somatotropin secreting cell development / growth hormone-releasing hormone activity / positive regulation of circadian sleep/wake cycle, non-REM sleep / water homeostasis / adenohypophysis development / positive regulation of growth hormone secretion ...positive regulation of circadian sleep/wake cycle, REM sleep / regulation of intracellular steroid hormone receptor signaling pathway / growth hormone-releasing hormone receptor binding / growth hormone-releasing hormone receptor activity / somatotropin secreting cell development / growth hormone-releasing hormone activity / positive regulation of circadian sleep/wake cycle, non-REM sleep / water homeostasis / adenohypophysis development / positive regulation of growth hormone secretion / growth hormone secretion / regulation of protein metabolic process / neuropeptide hormone activity / hormone metabolic process / intrinsic component of membrane / intracellular transport / hair follicle placode formation / positive regulation of multicellular organism growth / response to food / G protein-coupled peptide receptor activity / cardiac muscle cell apoptotic process / sensory perception of taste / multicellular organismal reproductive process / G-protein beta/gamma-subunit complex / cellular response to catecholamine stimulus / adenylate cyclase-activating adrenergic receptor signaling pathway / G-protein gamma-subunit binding / positive regulation of insulin-like growth factor receptor signaling pathway / alkylglycerophosphoethanolamine phosphodiesterase activity / nuclear inner membrane / growth factor binding / developmental growth / sensory perception of smell / positive regulation of cAMP-mediated signaling / nuclear outer membrane / peptide hormone receptor binding / adenylate cyclase-activating dopamine receptor signaling pathway / photoreceptor outer segment membrane / G-protein beta-subunit binding / peptide hormone binding / photoreceptor outer segment / spectrin binding / bone development / G-protein beta/gamma-subunit complex binding / cellular response to glucagon stimulus / heterotrimeric G-protein complex / renal water homeostasis / cAMP-mediated signaling / adenylate cyclase activator activity / activation of adenylate cyclase activity / G protein-coupled receptor activity / trans-Golgi network membrane / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / cellular response to prostaglandin E stimulus / response to insulin / phospholipase C-activating G protein-coupled receptor signaling pathway / determination of adult lifespan / adenylate cyclase-activating G protein-coupled receptor signaling pathway / GTPase binding / cell maturation / regulation of insulin secretion / retina development in camera-type eye / cognition / photoreceptor inner segment / lactation / cellular response to glucose stimulus / response to glucocorticoid / secretory granule / sarcolemma / platelet aggregation / nuclear matrix / terminal bouton / positive regulation of cold-induced thermogenesis / positive regulation of GTPase activity / cellular response to insulin stimulus / cell population proliferation / cell body / cell-cell signaling / positive regulation of cytosolic calcium ion concentration / cellular response to hypoxia / perikaryon / response to estrogen / cell surface receptor signaling pathway / GTPase activity / neuron projection / G protein-coupled receptor signaling pathway / GTP binding / dendrite / protein-containing complex binding / positive regulation of cell population proliferation / cell surface / extracellular space / extracellular exosome / membrane / integral component of membrane / extracellular region / plasma membrane / metal ion binding / cytosol / cytoplasm
Guanine nucleotide binding protein (G-protein), alpha subunit / GPCR, family 2, secretin-like, conserved site / WD40 repeat / G-protein, gamma subunit / GPCR, family 2, extracellular hormone receptor domain / GPCR, family 2, secretin-like / GPCR, family 2, growth hormone-releasing hormone receptor / G protein alpha subunit, helical insertion / G-protein gamma-like domain / WD40/YVTN repeat-like-containing domain superfamily ...Guanine nucleotide binding protein (G-protein), alpha subunit / GPCR, family 2, secretin-like, conserved site / WD40 repeat / G-protein, gamma subunit / GPCR, family 2, extracellular hormone receptor domain / GPCR, family 2, secretin-like / GPCR, family 2, growth hormone-releasing hormone receptor / G protein alpha subunit, helical insertion / G-protein gamma-like domain / WD40/YVTN repeat-like-containing domain superfamily / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / GPCR, family 2-like / G-protein alpha subunit, group S / WD40-repeat-containing domain / WD40-repeat-containing domain superfamily / WD40 repeat, conserved site / G-protein beta WD-40 repeat / Glucagon/GIP/secretin/VIP / P-loop containing nucleoside triphosphate hydrolase / G-protein gamma-like domain superfamily / GPCR family 2, extracellular hormone receptor domain superfamily
Somatoliberin / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Growth hormone-releasing hormone receptor
Biological speciesHomo sapiens (human)
Rattus norvegicus (Norway rat)
Bos taurus (cattle)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsZhou, F. / Zhang, H. / Cong, Z. / Zhao, L. / Zhou, Q. / Mao, C. / Cheng, X. / Shen, D. / Cai, X. / Ma, C. ...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.
CitationJournal: Nat Commun / Year: 2020
Title: Structural basis for activation of the growth hormone-releasing hormone receptor.
Authors: Fulai Zhou / Huibing Zhang / Zhaotong Cong / Li-Hua Zhao / Qingtong Zhou / Chunyou Mao / Xi Cheng / Dan-Dan Shen / Xiaoqing Cai / Cheng Ma / Yuzhe Wang / Antao Dai / Yan Zhou / Wen Sun / ...Authors: Fulai Zhou / Huibing Zhang / Zhaotong Cong / Li-Hua Zhao / Qingtong Zhou / Chunyou Mao / Xi Cheng / Dan-Dan Shen / Xiaoqing Cai / Cheng Ma / Yuzhe Wang / Antao Dai / Yan Zhou / Wen Sun / Fenghui Zhao / Suwen Zhao / Hualiang Jiang / Yi Jiang / Dehua Yang / H Eric Xu / Yan Zhang / Ming-Wei Wang /
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). ...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.
Validation Report
SummaryFull reportAbout validation report
History
DepositionSep 7, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 18, 2020Provider: repository / Type: Initial release

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Structure visualization

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Assembly

Deposited unit
R: Growth hormone-releasing hormone receptor,growth hormone-releasing hormone receptor
A: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
P: Somatoliberin
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
N: Nanobody35
hetero molecules


Theoretical massNumber of molelcules
Total (without water)178,5629
Polymers177,6636
Non-polymers9003
Water543
1


TypeNameSymmetry operationNumber
identity operation1_5551
Buried area16410 Å2
ΔGint-79 kcal/mol
Surface area46050 Å2

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Components

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Protein , 2 types, 2 molecules RN

#1: Protein Growth hormone-releasing hormone receptor,growth hormone-releasing hormone receptor / GHRH receptor / Growth hormone-releasing factor receptor / GRFR


Mass: 61651.438 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GHRHR / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q02643
#6: Protein Nanobody35


Mass: 13711.284 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG

#2: Protein Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Adenylate cyclase-stimulating G alpha protein


Mass: 45683.434 Da / Num. of mol.: 1
Mutation: S54N, G226A, E268A, N271K, K274D, R280K, T284D, I285T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAS, GNAS1, GSP / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63092
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 43706.750 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Gnb1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P54311
#5: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63212

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Protein/peptide , 1 types, 1 molecules P

#3: Protein/peptide Somatoliberin / Growth hormone-releasing factor / GRF / Growth hormone-releasing hormone / GHRH / Somatocrinin / Somatorelin


Mass: 5048.702 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P01286

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Non-polymers , 3 types, 6 molecules

#7: Chemical ChemComp-PLM / PALMITIC ACID / Palmitic acid


Mass: 256.424 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H32O2
#8: Chemical ChemComp-CLR / CHOLESTEROL / Cholesterol


Mass: 386.654 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H46O
#9: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeDetailsEntity IDParent-IDSource
1Growth hormone-releasing hormone receptor - Gs protein complexCOMPLEXgrowth hormone-releasing hormone growth hormone-releasing hormone receptor Gs protein Nanobody35#1-#60MULTIPLE SOURCES
2hormone receptor, G(s) subunit alpha isoformsCOMPLEX#1-#21RECOMBINANT
3hormoneCOMPLEX#31RECOMBINANT
4G(s) subunit beta-1COMPLEX#41RECOMBINANT
5G(s) subunit gamma-2COMPLEX#51RECOMBINANT
6Nanobody35COMPLEX#61RECOMBINANT
Molecular weightValue: 0.18 MDa / Experimental value: YES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
34Rattus norvegicus (Norway rat)10116
45Bos taurus (cattle)9913
56synthetic construct (others)32630
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Spodoptera frugiperda (fall armyworm)7108
23Spodoptera frugiperda (fall armyworm)7108
34Spodoptera frugiperda (fall armyworm)7108
45Spodoptera frugiperda (fall armyworm)7108
56Escherichia coli (E. coli)562
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 62 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.16_3549: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 307018 / Symmetry type: POINT
Refine LS restraints
Refinement-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0048508
ELECTRON MICROSCOPYf_angle_d0.60511518
ELECTRON MICROSCOPYf_dihedral_angle_d12.495035
ELECTRON MICROSCOPYf_chiral_restr0.0451292
ELECTRON MICROSCOPYf_plane_restr0.0041460

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