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- PDB-8thl: Cryo-EM structure of epinephrine-bound alpha-1A-adrenergic recept... -

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Basic information

Entry
Database: PDB / ID: 8thl
TitleCryo-EM structure of epinephrine-bound alpha-1A-adrenergic receptor in complex with heterotrimeric Gq-protein
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Endolysin,Alpha-1A adrenergic receptor
  • Single fab chain (scFv16)
KeywordsSIGNALING PROTEIN / Alpha-1A-adrenergic receptor / Epinephrine
Function / homology
Function and homology information


negative regulation of heart rate involved in baroreceptor response to increased systemic arterial blood pressure / alpha1-adrenergic receptor activity / norepinephrine-epinephrine vasoconstriction involved in regulation of systemic arterial blood pressure / positive regulation of heart rate by epinephrine-norepinephrine / positive regulation of the force of heart contraction by epinephrine-norepinephrine / pilomotor reflex / phospholipase C-activating adrenergic receptor signaling pathway / neuron-glial cell signaling / cell growth involved in cardiac muscle cell development / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion ...negative regulation of heart rate involved in baroreceptor response to increased systemic arterial blood pressure / alpha1-adrenergic receptor activity / norepinephrine-epinephrine vasoconstriction involved in regulation of systemic arterial blood pressure / positive regulation of heart rate by epinephrine-norepinephrine / positive regulation of the force of heart contraction by epinephrine-norepinephrine / pilomotor reflex / phospholipase C-activating adrenergic receptor signaling pathway / neuron-glial cell signaling / cell growth involved in cardiac muscle cell development / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / phospholipase C-activating G protein-coupled glutamate receptor signaling pathway / positive regulation of action potential / positive regulation of smooth muscle contraction / PLC beta mediated events / phospholipase C-activating serotonin receptor signaling pathway / negative regulation of calcium ion-dependent exocytosis / entrainment of circadian clock / regulation of platelet activation / G protein-coupled adenosine receptor signaling pathway / negative regulation of adenylate cyclase activity / positive regulation of urine volume / adult heart development / positive regulation of neural precursor cell proliferation / negative regulation of synaptic transmission / regulation of canonical Wnt signaling pathway / Adrenoceptors / glutamate receptor signaling pathway / positive regulation of cardiac muscle hypertrophy / gamma-aminobutyric acid signaling pathway / positive regulation of vasoconstriction / regulation of calcium ion transport / negative regulation of apoptotic signaling pathway / phototransduction, visible light / smooth muscle contraction / PKA activation in glucagon signalling / developmental growth / hair follicle placode formation / photoreceptor outer segment / neuropeptide signaling pathway / D1 dopamine receptor binding / postsynaptic cytosol / neuronal dense core vesicle / intracellular transport / vascular endothelial cell response to laminar fluid shear stress / viral release from host cell by cytolysis / renal water homeostasis / activation of adenylate cyclase activity / Hedgehog 'off' state / Adenylate cyclase inhibitory pathway / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of superoxide anion generation / response to hormone / adenylate cyclase-activating adrenergic receptor signaling pathway / response to prostaglandin E / enzyme regulator activity / peptidoglycan catabolic process / response to nutrient / positive regulation of cardiac muscle contraction / cellular response to glucagon stimulus / regulation of insulin secretion / negative regulation of autophagy / GTPase activator activity / hippocampal mossy fiber to CA3 synapse / adenylate cyclase activator activity / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / trans-Golgi network membrane / positive regulation of synaptic transmission, GABAergic / Regulation of insulin secretion / negative regulation of inflammatory response to antigenic stimulus / G protein-coupled receptor binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / bone development / caveola / G-protein beta/gamma-subunit complex binding / platelet aggregation / Olfactory Signaling Pathway / cognition / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / cell wall macromolecule catabolic process / ADP signalling through P2Y purinoceptor 12 / photoreceptor disc membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / blood coagulation / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion
Similarity search - Function
Alpha 1A adrenoceptor / G-protein alpha subunit, group Q / Adrenoceptor family / G-protein alpha subunit, group S / Endolysin T4 type / T4-type lysozyme / : / Glycoside hydrolase, family 24 / Phage lysozyme / Lysozyme domain superfamily ...Alpha 1A adrenoceptor / G-protein alpha subunit, group Q / Adrenoceptor family / G-protein alpha subunit, group S / Endolysin T4 type / T4-type lysozyme / : / Glycoside hydrolase, family 24 / Phage lysozyme / Lysozyme domain superfamily / G-protein alpha subunit, group I / YVTN repeat-like/Quinoprotein amine dehydrogenase / Serpentine type 7TM GPCR chemoreceptor Srsx / 7 Propeller / Methylamine Dehydrogenase; Chain H / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / Lysozyme-like domain superfamily / 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 / P-loop containing nucleotide triphosphate hydrolases / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Immunoglobulins / Immunoglobulin-like / Sandwich / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
L-EPINEPHRINE / Endolysin / Guanine nucleotide-binding protein G(i) subunit alpha-2 / Alpha-1A adrenergic receptor / Guanine nucleotide-binding protein G(q) subunit alpha / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
Similarity search - Component
Biological speciesHomo sapiens (human)
Enterobacteria phage T4 (virus)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsSu, M. / Huang, X.Y.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM138676 United States
American Heart Association23CDA1049353 United States
CitationJournal: Nat Commun / Year: 2023
Title: Structural basis of agonist specificity of α-adrenergic receptor.
Authors: Minfei Su / Jinan Wang / Guoqing Xiang / Hung Nguyen Do / Joshua Levitz / Yinglong Miao / Xin-Yun Huang /
Abstract: α-adrenergic receptors (α-ARs) play critical roles in the cardiovascular and nervous systems where they regulate blood pressure, cognition, and metabolism. However, the lack of specific agonists ...α-adrenergic receptors (α-ARs) play critical roles in the cardiovascular and nervous systems where they regulate blood pressure, cognition, and metabolism. However, the lack of specific agonists for all α subtypes has limited our understanding of the physiological roles of different α-AR subtypes, and led to the stagnancy in agonist-based drug development for these receptors. Here we report cryo-EM structures of α-AR in complex with heterotrimeric G-proteins and either the endogenous common agonist epinephrine or the α-AR-specific synthetic agonist A61603. These structures provide molecular insights into the mechanisms underlying the discrimination between α-AR and α-AR by A61603. Guided by the structures and corresponding molecular dynamics simulations, we engineer α-AR mutants that are not responsive to A61603, and α-AR mutants that can be potently activated by A61603. Together, these findings advance our understanding of the agonist specificity for α-ARs at the molecular level, opening the possibility of rational design of subtype-specific agonists.
History
DepositionJul 17, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 16, 2023Provider: repository / Type: Initial release
Revision 1.1May 1, 2024Group: Database references / Category: citation
Item: _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Nov 6, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(i) subunit alpha-2,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short,Guanine nucleotide-binding protein G(q) subunit alpha
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
F: Single fab chain (scFv16)
R: Endolysin,Alpha-1A adrenergic receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)160,7016
Polymers160,5185
Non-polymers1831
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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

#1: Protein Guanine nucleotide-binding protein G(i) subunit alpha-2,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short,Guanine nucleotide-binding protein G(q) subunit alpha / Adenylate cyclase-inhibiting G alpha protein / Adenylate cyclase-stimulating G alpha protein / ...Adenylate cyclase-inhibiting G alpha protein / Adenylate cyclase-stimulating G alpha protein / Guanine nucleotide-binding protein alpha-q


Mass: 28084.832 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI2, GNAI2B, GNAS, GNAS1, GSP, GNAQ, GAQ / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P04899, UniProt: P63092, UniProt: P50148
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 39418.086 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#3: 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.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Antibody / Protein / Non-polymers , 3 types, 3 molecules FR

#4: Antibody Single fab chain (scFv16)


Mass: 28668.922 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)
#5: Protein Endolysin,Alpha-1A adrenergic receptor / Lysis protein / Lysozyme / Muramidase / Alpha-1A adrenoreceptor / Alpha-1A adrenoceptor / Alpha-1C ...Lysis protein / Lysozyme / Muramidase / Alpha-1A adrenoreceptor / Alpha-1A adrenoceptor / Alpha-1C adrenergic receptor / Alpha-adrenergic receptor 1c


Mass: 56485.246 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Enterobacteria phage T4 (virus), (gene. exp.) Homo sapiens (human)
Gene: E, ADRA1A, ADRA1C / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P00720, UniProt: P35348, lysozyme
#6: Chemical ChemComp-ALE / L-EPINEPHRINE / ADRENALINE


Mass: 183.204 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H13NO3 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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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

ComponentName: Epinephrine-bound alpha-1A-adrenergic receptor in complex with heterotrimeric Gq-protein
Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Molecular weightValue: 0.16 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7
SpecimenConc.: 2.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen 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 FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 52 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 219834 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0038005
ELECTRON MICROSCOPYf_angle_d0.47110936
ELECTRON MICROSCOPYf_dihedral_angle_d9.7592642
ELECTRON MICROSCOPYf_chiral_restr0.0411291
ELECTRON MICROSCOPYf_plane_restr0.0031400

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