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- EMDB-31825: Cryo-EM structure of the GHRH-bound human GHRHR splice variant 1 ... -

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Entry
Database: EMDB / ID: EMD-31825
TitleCryo-EM structure of the GHRH-bound human GHRHR splice variant 1 complex
Map data
Sample
  • Complex: Cryo-EM structure of the human growth hormone releasing hormone receptor splice variant 1 in complex with GHRH and G protein
    • Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Nanobody-35
    • Protein or peptide: Somatoliberin
    • Protein or peptide: human growth hormone releasing hormone receptor splice variant 1(SV1)
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Keywordsclass B GPCR / receptor bias / cancer / cell proliferation / STRUCTURAL PROTEIN
Function / homology
Function and homology information


growth hormone-releasing hormone receptor binding / positive regulation of circadian sleep/wake cycle, REM sleep / growth hormone-releasing hormone activity / growth hormone secretion / adenohypophysis development / positive regulation of growth hormone secretion / neuropeptide hormone activity / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors ...growth hormone-releasing hormone receptor binding / positive regulation of circadian sleep/wake cycle, REM sleep / growth hormone-releasing hormone activity / growth hormone secretion / adenohypophysis development / positive regulation of growth hormone secretion / neuropeptide hormone activity / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / positive regulation of multicellular organism growth / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / G alpha (z) signalling events / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (i) signalling events / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / alkylglycerophosphoethanolamine phosphodiesterase activity / positive regulation of insulin-like growth factor receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / response to food / G alpha (q) signalling events / peptide hormone receptor binding / photoreceptor outer segment membrane / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / spectrin binding / Vasopressin regulates renal water homeostasis via Aquaporins / PKA activation in glucagon signalling / hair follicle placode formation / photoreceptor outer segment / developmental growth / D1 dopamine receptor binding / intracellular transport / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / cardiac muscle cell apoptotic process / adenylate cyclase activator activity / photoreceptor inner segment / trans-Golgi network membrane / G-protein beta/gamma-subunit complex binding / bone development / multicellular organism growth / adenylate cyclase-activating G protein-coupled receptor signaling pathway / terminal bouton / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / cognition / platelet aggregation / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / GPER1 signaling / G-protein beta-subunit binding / heterotrimeric G-protein complex / sensory perception of smell / signaling receptor complex adaptor activity / GTPase binding / cell-cell signaling / retina development in camera-type eye / positive regulation of cold-induced thermogenesis / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration
Similarity search - Function
: / Glucagon/GIP/secretin/VIP / Peptide hormone / Glucagon / GIP / secretin / VIP family signature. / Glucagon like hormones / G-protein alpha subunit, group S / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit ...: / Glucagon/GIP/secretin/VIP / Peptide hormone / Glucagon / GIP / secretin / VIP family signature. / Glucagon like hormones / G-protein alpha subunit, group S / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
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
Similarity search - Component
Biological speciesHomo sapiens (human) / Rattus norvegicus (Norway rat) / synthetic construct (others) / Bos taurus (cattle)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.29 Å
AuthorsCong ZT / Zhou FL
Funding support China, 5 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81872915 China
National Natural Science Foundation of China (NSFC)82073904 China
National Natural Science Foundation of China (NSFC)81773792 China
National Natural Science Foundation of China (NSFC)81973373 China
National Natural Science Foundation of China (NSFC)21704064 China
CitationJournal: Proc Natl Acad Sci U S A / Year: 2021
Title: Constitutive signal bias mediated by the human GHRHR splice variant 1.
Authors: Zhaotong Cong / Fulai Zhou / Chao Zhang / Xinyu Zou / Huibing Zhang / Yuzhe Wang / Qingtong Zhou / Xiaoqing Cai / Qiaofeng Liu / Jie Li / Lijun Shao / Chunyou Mao / Xi Wang / Jihong Wu / ...Authors: Zhaotong Cong / Fulai Zhou / Chao Zhang / Xinyu Zou / Huibing Zhang / Yuzhe Wang / Qingtong Zhou / Xiaoqing Cai / Qiaofeng Liu / Jie Li / Lijun Shao / Chunyou Mao / Xi Wang / Jihong Wu / Tian Xia / Li-Hua Zhao / Hualiang Jiang / Yan Zhang / H Eric Xu / Xi Cheng / Dehua Yang / Ming-Wei Wang /
Abstract: Alternative splicing of G protein-coupled receptors has been observed, but their functions are largely unknown. Here, we report that a splice variant (SV1) of the human growth hormone-releasing ...Alternative splicing of G protein-coupled receptors has been observed, but their functions are largely unknown. Here, we report that a splice variant (SV1) of the human growth hormone-releasing hormone receptor (GHRHR) is capable of transducing biased signal. Differing only at the receptor N terminus, GHRHR predominantly activates G while SV1 selectively couples to β-arrestins. Based on the cryogenic electron microscopy structures of SV1 in the state or GHRH-bound state in complex with the G protein, molecular dynamics simulations reveal that the N termini of GHRHR and SV1 differentiate the downstream signaling pathways, G versus β-arrestins. As suggested by mutagenesis and functional studies, it appears that GHRH-elicited signal bias toward β-arrestin recruitment is constitutively mediated by SV1. The level of SV1 expression in prostate cancer cells is also positively correlated with ERK1/2 phosphorylation but negatively correlated with cAMP response. Our findings imply that constitutive signal bias may be a mechanism that ensures cancer cell proliferation.
History
DepositionAug 26, 2021-
Header (metadata) releaseOct 20, 2021-
Map releaseOct 20, 2021-
UpdateJun 19, 2024-
Current statusJun 19, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.08
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.08
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  • Surface view with fitted model
  • Atomic models: PDB-7v9m
  • Surface level: 0.08
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7v9m
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_31825.png

Downloads & links

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Map

FileDownload / File: emd_31825.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.04 Å
Density
Contour LevelBy AUTHOR: 0.00694 / Movie #1: 0.08
Minimum - Maximum-0.01837471 - 1.9698566
Average (Standard dev.)0.0012240462 (±0.022414776)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 266.24 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.041.041.04
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z266.240266.240266.240
α/β/γ90.00090.00090.000
start NX/NY/NZ336210602
NX/NY/NZ227193139
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-0.0181.9700.001

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Supplemental data

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Sample components

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

EntireName: Cryo-EM structure of the human growth hormone releasing hormone receptor splice variant 1 in complex with GHRH and G protein
Components
  • Complex: Cryo-EM structure of the human growth hormone releasing hormone receptor splice variant 1 in complex with GHRH and G protein
    • Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Nanobody-35
    • Protein or peptide: Somatoliberin
    • Protein or peptide: human growth hormone releasing hormone receptor splice variant 1(SV1)
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Supramolecule #1: Cryo-EM structure of the human growth hormone releasing hormone r...

SupramoleculeName: Cryo-EM structure of the human growth hormone releasing hormone receptor splice variant 1 in complex with GHRH and G protein
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short

MacromoleculeName: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 45.683434 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKNTIVKQM RILHVNGFNG EGGEEDPQAA RSNSDGEKA TKVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPD FDFPPEFYEH AKALWEDEGV R ACYERSNE ...String:
MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKNTIVKQM RILHVNGFNG EGGEEDPQAA RSNSDGEKA TKVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPD FDFPPEFYEH AKALWEDEGV R ACYERSNE YQLIDCAQYF LDKIDVIKQA DYVPSDQDLL RCRVLTSGIF ETKFQVDKVN FHMFDVGAQR DERRKWIQCF ND VTAIIFV VASSSYNMVI REDNQTNRLQ AALKLFDSIW NNKWLRDTSV ILFLNKQDLL AEKVLAGKSK IEDYFPEFAR YTT PEDATP EPGEDPRVTR AKYFIRDEFL RISTASGDGR HYCYPHFTCA VDTENIRRVF NDCRDIIQRM HLRQYELL

UniProtKB: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short

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Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 40.226992 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGSLLQSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD ...String:
MGSLLQSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD TTCALWDIET GQQTTTFTGH TGDVMSLSLA PDTRLFVSGA CDASAKLWDV REGMCRQTFT GHESDINAIC FF PNGNAFA TGSDDATCRL FDLRADQELM TYSHDNIICG ITSVSFSKSG RLLLAGYDDF NCNVWDALKA DRAGVLAGHD NRV SCLGVT DDGMAVATGS WDSFLKIWNG SSGGGGSGGG GSSGVSGWRL FKKIS

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #3: Nanobody-35

MacromoleculeName: Nanobody-35 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 15.343019 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MAQVQLQESG GGLVQPGGSL RLSCAASGFT FSNYKMNWVR QAPGKGLEWV SDISQSGASI SYTGSVKGRF TISRDNAKNT LYLQMNSLK PEDTAVYYCA RCPAPFTRDC FDVTSTTYAY RGQGTQVTVS SHHHHHHEPE A

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Macromolecule #4: Somatoliberin

MacromoleculeName: Somatoliberin / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 5.048702 KDa
SequenceString:
YADAIFTNSY RKVLGQLSAR KLLQDIMSRQ QGESNQERGA RARL

UniProtKB: Somatoliberin

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Macromolecule #5: human growth hormone releasing hormone receptor splice variant 1(SV1)

MacromoleculeName: human growth hormone releasing hormone receptor splice variant 1(SV1)
type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 57.878441 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MVPGTPSPLL GRGKELWLES LACLPGAVKR DCTITGWSEP FPPYPVACPV PLELLAEEES YFSTVKIIYT VGHSISIVAL FVAITILVA LRRLHCPRNY VHTQLFTTFI LKAGAVFLKD AALFHSDDTD HCSFSTVLCK VSVAASHFAT MTNFSWLLAE A VYLNCLLA ...String:
MVPGTPSPLL GRGKELWLES LACLPGAVKR DCTITGWSEP FPPYPVACPV PLELLAEEES YFSTVKIIYT VGHSISIVAL FVAITILVA LRRLHCPRNY VHTQLFTTFI LKAGAVFLKD AALFHSDDTD HCSFSTVLCK VSVAASHFAT MTNFSWLLAE A VYLNCLLA STSPSSRRAF WWLVLAGWGL PVLFTGTWVS CKLAFEDIAC WDLDDTSPYW WIIKGPIVLS VGVNFGLFLN II RILVRKL EPAQGSLHTQ SQYWRLSKST LFLIPLFGIH YIIFNFLPDN AGLGIRLPLE LGLGSFQGFI VAILYCFLNQ EVR TEISRK WHGHDPELLP AWRTRGSSGG GGSGGGGSSG VFTLEDFVGD WEQTAAYNLD QVLEQGGVSS LLQNLAVSVT PIQR IVRSG ENALKIDIHV IIPYEGLSAD QMAQIEEVFK VVYPVDDHHF KVILPYGTLV IDGVTPNMLN YFGRPYEGIA VFDGK KITV TGTLWNGNKI IDERLITPDG SMLFRVTINS GGSENLYFQ

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Macromolecule #6: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Bos taurus (cattle)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 80.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: OTHER
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7cz5

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.29 Å / Resolution method: DIFFRACTION PATTERN/LAYERLINES / Number images used: 277500
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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