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- PDB-6k41: cryo-EM structure of alpha2BAR-GoA complex -

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Basic information

Entry
Database: PDB / ID: 6k41
Titlecryo-EM structure of alpha2BAR-GoA complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Alpha-2A adrenergic receptor,Endolysin,Alpha-2B adrenergic receptor,Alpha-2B adrenergic receptor
  • scFvSingle-chain variable fragment
KeywordsMEMBRANE PROTEIN / GPCR / Complex / cryo-EM
Function / homology
Function and homology information


Activation of the phototransduction cascade / Sensory perception of sweet, bitter, and umami (glutamate) taste / regulation of vascular associated smooth muscle contraction / Olfactory Signaling Pathway / adenylate cyclase-inhibiting adrenergic receptor signaling pathway / phospholipase C-activating adrenergic receptor signaling pathway / alpha2-adrenergic receptor activity / Adrenaline signalling through Alpha-2 adrenergic receptor / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors ...Activation of the phototransduction cascade / Sensory perception of sweet, bitter, and umami (glutamate) taste / regulation of vascular associated smooth muscle contraction / Olfactory Signaling Pathway / adenylate cyclase-inhibiting adrenergic receptor signaling pathway / phospholipase C-activating adrenergic receptor signaling pathway / alpha2-adrenergic receptor activity / Adrenaline signalling through Alpha-2 adrenergic receptor / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / alpha-2C adrenergic receptor binding / receptor transactivation / epinephrine binding / Prostacyclin signalling through prostacyclin receptor / G alpha (z) signalling events / Glucagon-type ligand receptors / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / G beta:gamma signalling through BTK / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / positive regulation of uterine smooth muscle contraction / Thromboxane signalling through TP receptor / negative regulation of norepinephrine secretion / positive regulation of epidermal growth factor-activated receptor activity / Thrombin signalling through proteinase activated receptors (PARs) / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Ca2+ pathway / G alpha (s) signalling events / negative regulation of epinephrine secretion / G alpha (q) signalling events / Extra-nuclear estrogen signaling / G alpha (12/13) signalling events / heterotrimeric G-protein binding / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (i) signalling events / GPER1 signaling / dopaminergic synapse / regulation of smooth muscle contraction / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADP signalling through P2Y purinoceptor 1 / mu-type opioid receptor binding / phototransduction, visible light / corticotropin-releasing hormone receptor 1 binding / positive regulation of blood pressure / fear response / thioesterase binding / negative regulation of insulin secretion involved in cellular response to glucose stimulus / alkylglycerophosphoethanolamine phosphodiesterase activity / norepinephrine binding / Adrenoceptors / positive regulation of membrane protein ectodomain proteolysis / photoreceptor outer segment membrane / dopamine receptor signaling pathway / regulation of synaptic vesicle exocytosis / spectrin binding / positive regulation of wound healing / adrenergic receptor signaling pathway / plasma membrane => GO:0005886 / regulation of vasoconstriction / photoreceptor outer segment / G protein-coupled serotonin receptor binding / negative regulation of lipid catabolic process / adenylate cyclase-activating adrenergic receptor signaling pathway / viral release from host cell by cytolysis / cellular response to hormone stimulus / cardiac muscle cell apoptotic process / photoreceptor inner segment / positive regulation of neuron differentiation / activation of protein kinase B activity / peptidoglycan catabolic process / muscle contraction / female pregnancy / G protein-coupled receptor activity / positive regulation of cytokine production / G-protein beta/gamma-subunit complex binding / positive regulation of MAP kinase activity / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / platelet activation / Adrenaline,noradrenaline inhibits insulin secretion / 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
Similarity search - Function
Alpha 2B adrenoceptor / Alpha 2A adrenoceptor / Transducin (heterotrimeric G protein), gamma chain / G Protein Gi Gamma 2 / Adrenoceptor family / Rhopdopsin 7-helix transmembrane proteins / Rhodopsin 7-helix transmembrane proteins / YVTN repeat-like/Quinoprotein amine dehydrogenase / G-protein alpha subunit, group I / Endolysin T4 type ...Alpha 2B adrenoceptor / Alpha 2A adrenoceptor / Transducin (heterotrimeric G protein), gamma chain / G Protein Gi Gamma 2 / Adrenoceptor family / Rhopdopsin 7-helix transmembrane proteins / Rhodopsin 7-helix transmembrane proteins / YVTN repeat-like/Quinoprotein amine dehydrogenase / G-protein alpha subunit, group I / Endolysin T4 type / T4-type lysozyme / Glycoside hydrolase, family 24 / Lysozyme domain superfamily / Phage lysozyme / 7 Propeller / Methylamine Dehydrogenase; Chain H / 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) / Few Secondary Structures / Irregular / Lysozyme-like domain superfamily / 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 / Up-down Bundle / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Chem-CZX / Endolysin / Guanine nucleotide-binding protein G(o) subunit alpha / Alpha-2B adrenergic receptor / 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 / Alpha-2A adrenergic receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
Bos taurus (cattle)
Enterobacteria phage RB59 (virus)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsYuan, D. / Liu, Z. / Wang, H.W. / Kobilka, B.K.
CitationJournal: Nat Chem Biol / Year: 2020
Title: Activation of the α adrenoceptor by the sedative sympatholytic dexmedetomidine.
Authors: Daopeng Yuan / Zhongmin Liu / Jonas Kaindl / Shoji Maeda / Jiawei Zhao / Xiaoou Sun / Jun Xu / Peter Gmeiner / Hong-Wei Wang / Brian K Kobilka /
Abstract: The α adrenergic receptors (αARs) are G protein-coupled receptors (GPCRs) that respond to adrenaline and noradrenaline and couple to the Gi/o family of G proteins. αARs play important roles in ...The α adrenergic receptors (αARs) are G protein-coupled receptors (GPCRs) that respond to adrenaline and noradrenaline and couple to the Gi/o family of G proteins. αARs play important roles in regulating the sympathetic nervous system. Dexmedetomidine is a highly selective αAR agonist used in post-operative patients as an anxiety-reducing, sedative medicine that decreases the requirement for opioids. As is typical for selective αAR agonists, dexmedetomidine consists of an imidazole ring and a substituted benzene moiety lacking polar groups, which is in contrast to βAR-selective agonists, which share an ethanolamine group and an aromatic system with polar, hydrogen-bonding substituents. To better understand the structural basis for the selectivity and efficacy of adrenergic agonists, we determined the structure of the αAR in complex with dexmedetomidine and Go at a resolution of 2.9 Å by single-particle cryo-EM. The structure reveals the mechanism of αAR-selective activation and provides insights into Gi/o coupling specificity.
History
DepositionMay 23, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 15, 2020Provider: repository / Type: Initial release
Revision 1.1May 6, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2May 13, 2020Group: Structure summary / Category: audit_author / Item: _audit_author.name

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Structure visualization

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(o) 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
R: Alpha-2A adrenergic receptor,Endolysin,Alpha-2B adrenergic receptor,Alpha-2B adrenergic receptor
H: scFv
hetero molecules


Theoretical massNumber of molelcules
Total (without water)177,6206
Polymers177,4205
Non-polymers2001
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area10530 Å2
ΔGint-57 kcal/mol
Surface area47910 Å2

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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(o) subunit alpha


Mass: 40100.500 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAO1 / Production host: Spodoptera (butterflies/moths) / References: UniProt: P09471
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 38402.867 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Gnb1 / Production host: Spodoptera (butterflies/moths) / References: UniProt: P62874
#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 (butterflies/moths) / References: UniProt: P59768

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

#4: Protein Alpha-2A adrenergic receptor,Endolysin,Alpha-2B adrenergic receptor,Alpha-2B adrenergic receptor / Alpha-2A adrenoreceptor / Alpha-2AAR / Alpha-2D adrenergic receptor / Lysis protein / Lysozyme / ...Alpha-2A adrenoreceptor / Alpha-2AAR / Alpha-2D adrenergic receptor / Lysis protein / Lysozyme / Muramidase / Alpha-2 adrenergic receptor subtype C2 / Alpha-2B adrenoreceptor / Alpha-2BAR / Alpha-2 adrenergic receptor subtype C2 / Alpha-2B adrenoreceptor / Alpha-2BAR


Mass: 58156.211 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle), (gene. exp.) Enterobacteria phage RB59 (virus), (gene. exp.) Homo sapiens (human)
Gene: ADRA2A, e, RB59_126, ADRA2B, ADRA2L1, ADRA2RL1 / Production host: Spodoptera (butterflies/moths)
References: UniProt: Q28838, UniProt: A0A097J809, UniProt: P18089, lysozyme
#5: Antibody scFv / Single-chain variable fragment


Mass: 32898.781 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera (butterflies/moths)
#6: Chemical ChemComp-CZX / 4-[(1~{S})-1-(2,3-dimethylphenyl)ethyl]-1~{H}-imidazole / Dexmedetomidine


Mass: 200.280 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H16N2

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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: alpha2BAR-GoA complex / Type: COMPLEX / Entity ID: #1-#5 / Source: MULTIPLE SOURCES
Molecular weightValue: 0.15 MDa / Experimental value: YES
Source (natural)Organism: Spodoptera (butterflies/moths)
Buffer solutionpH: 7.5
SpecimenConc.: 10 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 R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 %

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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: SPOT SCAN
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 50 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.13_2998: / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 258283 / Symmetry type: POINT

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