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- PDB-8thk: Cryo-EM structure of A61603-bound alpha-1A-adrenergic receptor in... -
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Basic information
Entry | Database: PDB / ID: 8thk | |||||||||
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Title | Cryo-EM structure of A61603-bound alpha-1A-adrenergic receptor in complex with heterotrimeric Gq-protein | |||||||||
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![]() | SIGNALING PROTEIN / Alpha-1A-adrenergic receptor / A61603 | |||||||||
Function / homology | ![]() negative regulation of heart rate involved in baroreceptor response to increased systemic arterial blood pressure / alpha1-adrenergic receptor activity / positive regulation of the force of heart contraction by epinephrine-norepinephrine / norepinephrine-epinephrine vasoconstriction involved in regulation of systemic arterial blood pressure / pilomotor reflex / positive regulation of heart rate by epinephrine-norepinephrine / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway involved in heart process / neuron-glial cell signaling / cell growth involved in cardiac muscle cell development / positive regulation of protein kinase C signaling ...negative regulation of heart rate involved in baroreceptor response to increased systemic arterial blood pressure / alpha1-adrenergic receptor activity / positive regulation of the force of heart contraction by epinephrine-norepinephrine / norepinephrine-epinephrine vasoconstriction involved in regulation of systemic arterial blood pressure / pilomotor reflex / positive regulation of heart rate by epinephrine-norepinephrine / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway involved in heart process / neuron-glial cell signaling / cell growth involved in cardiac muscle cell development / positive regulation of protein kinase C signaling / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / positive regulation of action potential / G protein-coupled adenosine receptor signaling pathway / PLC beta mediated events / phospholipase C-activating dopamine receptor signaling pathway / negative regulation of calcium ion-dependent exocytosis / entrainment of circadian clock / regulation of platelet activation / positive regulation of smooth muscle contraction / positive regulation of urine volume / phototransduction, visible light / negative regulation of adenylate cyclase activity / adult heart development / positive regulation of neural precursor cell proliferation / glutamate receptor signaling pathway / gamma-aminobutyric acid signaling pathway / : / regulation of canonical Wnt signaling pathway / negative regulation of synaptic transmission / Adrenoceptors / calcium ion transport into cytosol / positive regulation of cardiac muscle hypertrophy / neuronal dense core vesicle / action potential / PKA activation in glucagon signalling / regulation of calcium ion transport / positive regulation of vasoconstriction / hair follicle placode formation / negative regulation of apoptotic signaling pathway / smooth muscle contraction / photoreceptor outer segment / developmental growth / D1 dopamine receptor binding / intracellular transport / Adenylate cyclase inhibitory pathway / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / response to nutrient / positive regulation of insulin receptor signaling pathway / positive regulation of superoxide anion generation / viral release from host cell by cytolysis / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of cardiac muscle contraction / adenylate cyclase activator activity / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / peptidoglycan catabolic process / GTPase activator activity / negative regulation of autophagy / response to hormone / trans-Golgi network membrane / caveola / Regulation of insulin secretion / positive regulation of synaptic transmission, GABAergic / G protein-coupled receptor binding / negative regulation of protein kinase activity / G-protein beta/gamma-subunit complex binding / bone development / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G protein-coupled acetylcholine 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 / cognition / platelet aggregation / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / 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 / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma Similarity search - Function | |||||||||
Biological species | ![]() ![]() | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.6 Å | |||||||||
![]() | Su, M. / Huang, X.Y. | |||||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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PDBx/mmCIF format | ![]() | 227.6 KB | Display | ![]() |
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PDB format | ![]() | 171.1 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 41267MC ![]() 8thlC M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Components
-Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG
#1: Protein | Mass: 28084.832 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() References: UniProt: P04899, UniProt: P63092, UniProt: P50148 |
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#2: Protein | Mass: 39418.086 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
#3: Protein | Mass: 7861.143 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
-Antibody / Protein / Non-polymers , 3 types, 3 molecules FR![](data/chem/img/CGZ.gif)
![](data/chem/img/CGZ.gif)
#4: Antibody | Mass: 28668.922 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
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#5: Protein | Mass: 56485.246 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() Gene: E, ADRA1A, ADRA1C / Production host: ![]() ![]() |
#6: Chemical | ChemComp-CGZ / |
-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: A61603-bound alpha-1A-adrenergic receptor in complex with heterotrimeric Gq-protein Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT |
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Molecular weight | Value: 0.16 MDa / Experimental value: NO |
Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() ![]() |
Buffer solution | pH: 7 |
Specimen | Conc.: 2.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 1000 nm |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
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Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
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3D reconstruction | Resolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 360489 / Symmetry type: POINT | ||||||||||||||||||||||||
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