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- PDB-7jjo: Structural Basis of the Activation of Heterotrimeric Gs-protein b... -

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Basic information

Entry
Database: PDB / ID: 7jjo
TitleStructural Basis of the Activation of Heterotrimeric Gs-protein by Isoproterenol-bound Beta1-Adrenergic Receptor
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Beta1-Adrenergic Receptor
  • Nanobody 35Single-domain antibody
KeywordsSIGNALING PROTEIN / Gs protein / GPCR-Gs complex / Agonist
Function / homology
Function and homology information


beta1-adrenergic receptor activity / positive regulation of heart contraction / Olfactory Signaling Pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / regulation of circadian sleep/wake cycle, sleep / sensory perception of chemical stimulus / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / Activation of the phototransduction cascade ...beta1-adrenergic receptor activity / positive regulation of heart contraction / Olfactory Signaling Pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / regulation of circadian sleep/wake cycle, sleep / sensory perception of chemical stimulus / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / Activation of the phototransduction cascade / 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 / 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 / beta-2 adrenergic receptor binding / G alpha (q) signalling events / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / D1 dopamine receptor binding / positive regulation of cAMP-mediated signaling / adenylate cyclase-activating adrenergic receptor signaling pathway / ionotropic glutamate receptor binding / insulin-like growth factor receptor binding / adenylate cyclase activator activity / G-protein beta/gamma-subunit complex binding / adenylate cyclase-activating G protein-coupled receptor signaling pathway / photoreceptor disc membrane / positive regulation of GTPase activity / cellular response to catecholamine stimulus / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / sensory perception of taste / G-protein beta-subunit binding / heterotrimeric G-protein complex / signaling receptor complex adaptor activity / retina development in camera-type eye / GTPase binding / phospholipase C-activating G protein-coupled receptor signaling pathway / cell population proliferation / early endosome / G protein-coupled receptor signaling pathway / GTPase activity / protein-containing complex binding / GTP binding / membrane / identical protein binding / metal ion binding / plasma membrane / cytoplasm
Similarity search - Function
Beta 1 adrenoceptor / Adrenoceptor family / G-protein alpha subunit, group S / Serpentine type 7TM GPCR chemoreceptor Srsx / 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 ...Beta 1 adrenoceptor / Adrenoceptor family / G-protein alpha subunit, group S / Serpentine type 7TM GPCR chemoreceptor Srsx / 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 coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
ISOPRENALINE / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Beta-1 adrenergic receptor / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Similarity search - Component
Biological speciesBos taurus (cattle)
Lama glama (llama)
Meleagris gallopavo (turkey)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsSu, M. / Zhu, L. / Zhang, Y. / Paknejad, N. / Dey, R. / Huang, J. / Lee, M.Y. / Williams, D. / Jordan, K.D. / Eng, E.T. ...Su, M. / Zhu, L. / Zhang, Y. / Paknejad, N. / Dey, R. / Huang, J. / Lee, M.Y. / Williams, D. / Jordan, K.D. / Eng, E.T. / Ernst, O.P. / Meyerson, J.R. / Hite, R.K. / Walz, T. / Liu, W. / Huang, X.Y.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL130478 United States
CitationJournal: Mol Cell / Year: 2020
Title: Structural Basis of the Activation of Heterotrimeric Gs-Protein by Isoproterenol-Bound β-Adrenergic Receptor.
Authors: Minfei Su / Lan Zhu / Yixiao Zhang / Navid Paknejad / Raja Dey / Jianyun Huang / Ming-Yue Lee / Dewight Williams / Kelsey D Jordan / Edward T Eng / Oliver P Ernst / Joel R Meyerson / Richard ...Authors: Minfei Su / Lan Zhu / Yixiao Zhang / Navid Paknejad / Raja Dey / Jianyun Huang / Ming-Yue Lee / Dewight Williams / Kelsey D Jordan / Edward T Eng / Oliver P Ernst / Joel R Meyerson / Richard K Hite / Thomas Walz / Wei Liu / Xin-Yun Huang /
Abstract: Cardiac disease remains the leading cause of morbidity and mortality worldwide. The β-adrenergic receptor (β-AR) is a major regulator of cardiac functions and is downregulated in the majority of ...Cardiac disease remains the leading cause of morbidity and mortality worldwide. The β-adrenergic receptor (β-AR) is a major regulator of cardiac functions and is downregulated in the majority of heart failure cases. A key physiological process is the activation of heterotrimeric G-protein Gs by β-ARs, leading to increased heart rate and contractility. Here, we use cryo-electron microscopy and functional studies to investigate the molecular mechanism by which β-AR activates Gs. We find that the tilting of α5-helix breaks a hydrogen bond between the sidechain of His373 in the C-terminal α5-helix and the backbone carbonyl of Arg38 in the N-terminal αN-helix of Gα. Together with the disruption of another interacting network involving Gln59 in the α1-helix, Ala352 in the β6-α5 loop, and Thr355 in the α5-helix, these conformational changes might lead to the deformation of the GDP-binding pocket. Our data provide molecular insights into the activation of G-proteins by G-protein-coupled receptors.
History
DepositionJul 27, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 2, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 14, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.title

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Structure visualization

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Assembly

Deposited unit
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
N: Nanobody 35
A: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
R: Beta1-Adrenergic Receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)163,1366
Polymers162,9255
Non-polymers2111
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area12030 Å2
ΔGint-64 kcal/mol
Surface area44450 Å2

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Components

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

#1: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37285.734 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62871
#3: Protein Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Adenylate cyclase-stimulating G alpha protein


Mass: 44694.551 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Gene: GNAS, GNAS1 / Production host: Escherichia coli (E. coli) / References: UniProt: P04896
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7845.078 Da / Num. of mol.: 1 / Mutation: C68S
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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Antibody / Protein / Non-polymers , 3 types, 3 molecules NR

#2: Antibody Nanobody 35 / Single-domain antibody


Mass: 15140.742 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)
#5: Protein Beta1-Adrenergic Receptor


Mass: 57958.668 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Meleagris gallopavo (turkey) / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P07700*PLUS
#6: Chemical ChemComp-5FW / ISOPRENALINE / Isoprenaline


Mass: 211.258 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H17NO3 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, agonist*YM

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Details

Has ligand of interestY

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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
IDNameTypeEntity IDParent-IDSource
1Isoproterenol bound beta1 adrenergic receptor in complex with heterotrimeric Gs proteinCOMPLEX#1-#50MULTIPLE SOURCES
2Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2COMPLEX#1, #41RECOMBINANT
3Nanobody 35Single-domain antibodyCOMPLEX#21RECOMBINANT
4Guanine nucleotide-binding protein G(s) subunit alpha isoforms shortCOMPLEX#31RECOMBINANT
5Beta1-Adrenergic ReceptorCOMPLEX#51RECOMBINANT
Molecular weightValue: 0.16 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Bos taurus (cattle)9913
23Lama glama (llama)9844
34Bos taurus (cattle)9913
45Meleagris gallopavo (turkey)9103
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Spodoptera frugiperda (fall armyworm)7108
23Escherichia coli (E. coli)562
34Escherichia coli (E. coli)562
45Spodoptera frugiperda (fall armyworm)7108
Buffer solutionpH: 7
SpecimenConc.: 1.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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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: 46 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
10cryoSPARCv2initial Euler assignment
11cryoSPARCv2final Euler assignment
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 452312 / Symmetry type: POINT

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