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- EMDB-30505: Cryo-EM structure of the human growth hormone-releasing hormone r... -

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Basic information

Entry
Database: EMDB / ID: EMD-30505
TitleCryo-EM structure of the human growth hormone-releasing hormone receptor-Gs protein complex
Map data
SampleGrowth hormone-releasing hormone receptor - Gs protein complex
  • hormone receptor, G(s) subunit alpha isoforms
  • hormone
  • (G(s) subunit ...) x 2
  • (Nanobody35) x 2
  • Growth hormone-releasing hormone receptor,growth hormone-releasing hormone receptor
  • (Guanine nucleotide-binding protein ...) x 3
  • Somatoliberin
  • (ligand) x 3
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)
Methodsingle 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 HE / 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 ReportPDB-ID: 7cz5

SummaryFull reportAbout validation report
History
DepositionSep 7, 2020-
Header (metadata) releaseNov 18, 2020-
Map releaseNov 18, 2020-
UpdateNov 18, 2020-
Current statusNov 18, 2020Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.04
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.04
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7cz5
  • Surface level: 0.04
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_30505.map.gz / Format: CCP4 / Size: 42.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.01 Å/pix.
x 224 pix.
= 227.136 Å
1.01 Å/pix.
x 224 pix.
= 227.136 Å
1.01 Å/pix.
x 224 pix.
= 227.136 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.014 Å
Density
Contour LevelBy AUTHOR: 0.04 / Movie #1: 0.04
Minimum - Maximum-0.14674748 - 0.27302492
Average (Standard dev.)-0.0000094593 (±0.0064187776)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions224224224
Spacing224224224
CellA=B=C: 227.13602 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0141.0141.014
M x/y/z224224224
origin x/y/z0.0000.0000.000
length x/y/z227.136227.136227.136
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ256256256
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS224224224
D min/max/mean-0.1470.273-0.000

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Supplemental data

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Sample components

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Entire Growth hormone-releasing hormone receptor - Gs protein complex

EntireName: Growth hormone-releasing hormone receptor - Gs protein complex
Details: growth hormone-releasing hormone growth hormone-releasing hormone receptor Gs protein Nanobody35
Number of components: 15

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Component #1: protein, Growth hormone-releasing hormone receptor - Gs protein c...

ProteinName: Growth hormone-releasing hormone receptor - Gs protein complex
Details: growth hormone-releasing hormone growth hormone-releasing hormone receptor Gs protein Nanobody35
Recombinant expression: No
MassExperimental: 180 kDa

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Component #2: protein, hormone receptor, G(s) subunit alpha isoforms

ProteinName: hormone receptor, G(s) subunit alpha isoforms / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #3: protein, hormone

ProteinName: hormone / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #4: protein, G(s) subunit beta-1

ProteinName: G(s) subunit beta-1 / Recombinant expression: No
SourceSpecies: Rattus norvegicus (Norway rat)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #5: protein, G(s) subunit gamma-2

ProteinName: G(s) subunit gamma-2 / Recombinant expression: No
SourceSpecies: Bos taurus (cattle)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #6: protein, Nanobody35

ProteinName: Nanobody35 / Recombinant expression: No
SourceSpecies: synthetic construct (others)
Source (engineered)Expression System: Escherichia coli (E. coli)

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Component #7: protein, Growth hormone-releasing hormone receptor,growth hormone...

ProteinName: Growth hormone-releasing hormone receptor,growth hormone-releasing hormone receptor
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 61.651438 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #8: protein, Guanine nucleotide-binding protein G(s) subunit alpha is...

ProteinName: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 45.683434 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #9: protein, Somatoliberin

ProteinName: Somatoliberin / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 5.048702 kDa
SourceSpecies: Homo sapiens (human)

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Component #10: protein, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subuni...

ProteinName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 43.70675 kDa
SourceSpecies: Rattus norvegicus (Norway rat)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #11: protein, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subuni...

ProteinName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 7.861143 kDa
SourceSpecies: Bos taurus (cattle)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #12: protein, Nanobody35

ProteinName: Nanobody35 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 13.711284 kDa
SourceSpecies: synthetic construct (others)
Source (engineered)Expression System: Escherichia coli (E. coli)

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Component #13: ligand, PALMITIC ACID

LigandName: PALMITIC ACID / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 0.256424 kDa

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Component #14: ligand, CHOLESTEROL

LigandName: CHOLESTEROL / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 0.386654 kDa

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Component #15: ligand, water

LigandName: water / Number of Copies: 3 / Recombinant expression: No
MassTheoretical: 1.801505 MDa

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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 62 e/Å2 / Illumination mode: FLOOD BEAM
LensImaging mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: GATAN K2 QUANTUM (4k x 4k)

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Image processing

ProcessingMethod: single particle reconstruction / Number of projections: 307018
3D reconstructionResolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF

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Atomic model buiding

Output model

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