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Yorodumi- EMDB-31147: Structure of the alpha2A-adrenergic receptor GoA signaling complex -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-31147 | |||||||||
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Title | Structure of the alpha2A-adrenergic receptor GoA signaling complex | |||||||||
Map data | 3.2 angstrom alpha2A-Go complex bound to norepi | |||||||||
Sample |
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Function / homology | Function and homology information negative regulation of uterine smooth muscle contraction / 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 / alpha-2C adrenergic receptor binding / receptor transactivation / epinephrine binding / alpha-1B adrenergic receptor binding / negative regulation of norepinephrine secretion ...negative regulation of uterine smooth muscle contraction / 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 / alpha-2C adrenergic receptor binding / receptor transactivation / epinephrine binding / alpha-1B adrenergic receptor binding / negative regulation of norepinephrine secretion / negative regulation of calcium ion transmembrane transporter activity / negative regulation of epinephrine secretion / heterotrimeric G-protein binding / negative regulation of calcium ion-dependent exocytosis / dopaminergic synapse / mu-type opioid receptor binding / Surfactant metabolism / positive regulation of potassium ion transport / corticotropin-releasing hormone receptor 1 binding / thermoception / fear response / thioesterase binding / negative regulation of insulin secretion involved in cellular response to glucose stimulus / vesicle docking involved in exocytosis / intestinal absorption / positive regulation of membrane protein ectodomain proteolysis / norepinephrine binding / Adrenoceptors / positive regulation of epidermal growth factor receptor signaling pathway / G protein-coupled dopamine receptor signaling pathway / regulation of heart contraction / positive regulation of wound healing / activation of protein kinase activity / adrenergic receptor signaling pathway / adenylate cyclase-activating adrenergic receptor signaling pathway / negative regulation of calcium ion transport / Rho protein signal transduction / regulation of vasoconstriction / negative regulation of insulin secretion / negative regulation of lipid catabolic process / G protein-coupled serotonin receptor binding / GABA-ergic synapse / muscle contraction / cellular response to hormone stimulus / presynaptic active zone membrane / axon terminus / presynaptic modulation of chemical synaptic transmission / activation of protein kinase B activity / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / positive regulation of cytokine production / female pregnancy / locomotory behavior / adenylate cyclase-activating G protein-coupled receptor signaling pathway / postsynaptic density membrane / positive regulation of MAP kinase activity / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Glucagon signaling in metabolic regulation / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / platelet activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G beta:gamma signalling through CDC42 / Vasopressin regulates renal water homeostasis via Aquaporins / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / G alpha (z) signalling events / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / vasodilation / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / GPER1 signaling / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / glucose homeostasis / retina development in camera-type eye Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / Mus musculus (house mouse) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.2 Å | |||||||||
Authors | Xu J / Cao S / Liu Z / Du Y | |||||||||
Citation | Journal: Sci Adv / Year: 2022 Title: Structural insights into ligand recognition, activation, and signaling of the α adrenergic receptor. Authors: Jun Xu / Sheng Cao / Harald Hübner / Dorothée Weikert / Geng Chen / Qiuyuan Lu / Daopeng Yuan / Peter Gmeiner / Zheng Liu / Yang Du / Abstract: The α adrenergic receptor (αAR) is a G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor that mediates important physiological functions in response to the endogenous ...The α adrenergic receptor (αAR) is a G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor that mediates important physiological functions in response to the endogenous neurotransmitters norepinephrine and epinephrine, as well as numerous chemically distinct drugs. However, the molecular mechanisms of drug actions remain poorly understood. Here, we report the cryo-electron microscopy structures of the human αAR-GoA complex bound to norepinephrine and three imidazoline derivatives (brimonidine, dexmedetomidine, and oxymetazoline). Together with mutagenesis and functional data, these structures provide important insights into the molecular basis of ligand recognition, activation, and signaling at the αAR. Further structural analyses uncover different molecular determinants between αAR and βARs for recognition of norepinephrine and key regions that determine the G protein coupling selectivity. Overall, our studies provide a framework for understanding the signal transduction of the adrenergic system at the atomic level, which will facilitate rational structure-based discovery of safer and more effective medications for αAR. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_31147.map.gz | 59.5 MB | EMDB map data format | |
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Header (meta data) | emd-31147-v30.xml emd-31147.xml | 17 KB 17 KB | Display Display | EMDB header |
Images | emd_31147.png | 62.8 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-31147 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-31147 | HTTPS FTP |
-Validation report
Summary document | emd_31147_validation.pdf.gz | 531.7 KB | Display | EMDB validaton report |
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Full document | emd_31147_full_validation.pdf.gz | 531.3 KB | Display | |
Data in XML | emd_31147_validation.xml.gz | 6.4 KB | Display | |
Data in CIF | emd_31147_validation.cif.gz | 7.3 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-31147 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-31147 | HTTPS FTP |
-Related structure data
Related structure data | 7ej0MC 7ej8C 7ejaC 7ejkC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_31147.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Annotation | 3.2 angstrom alpha2A-Go complex bound to norepi | ||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.85 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Sample components
-Entire : alpha2A-adrenergic receptor Go signaling complex
Entire | Name: alpha2A-adrenergic receptor Go signaling complex |
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Components |
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-Supramolecule #1: alpha2A-adrenergic receptor Go signaling complex
Supramolecule | Name: alpha2A-adrenergic receptor Go signaling complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5 |
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-Supramolecule #2: alpha2A-adrenergic receptor Go signaling complex
Supramolecule | Name: alpha2A-adrenergic receptor Go signaling complex / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#3, #5 |
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Source (natural) | Organism: Homo sapiens (human) |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
-Supramolecule #3: scFv16
Supramolecule | Name: scFv16 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #4 |
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Source (natural) | Organism: Mus musculus (house mouse) |
Recombinant expression | Organism: Trichoplusia ni (cabbage looper) |
-Macromolecule #1: Guanine nucleotide-binding protein G(o) subunit alpha
Macromolecule | Name: Guanine nucleotide-binding protein G(o) subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 40.1005 KDa |
Recombinant expression | Organism: Trichoplusia ni (cabbage looper) |
Sequence | String: MGCTLSAEER AALERSKAIE KNLKEDGISA AKDVKLLLLG AGESGKSTIV KQMKIIHEDG FSGEDVKQYK PVVYSNTIQS LAAIVRAMD TLGIEYGDKE RKADAKMVCD VVSRMEDTEP FSAELLSAMM RLWGDSGIQE CFNRSREYQL NDSAKYYLDS L DRIGAADY ...String: MGCTLSAEER AALERSKAIE KNLKEDGISA AKDVKLLLLG AGESGKSTIV KQMKIIHEDG FSGEDVKQYK PVVYSNTIQS LAAIVRAMD TLGIEYGDKE RKADAKMVCD VVSRMEDTEP FSAELLSAMM RLWGDSGIQE CFNRSREYQL NDSAKYYLDS L DRIGAADY QPTEQDILRT RVKTTGIVET HFTFKNLHFR LFDVGGQRSE RKKWIHCFED VTAIIFCVAL SGYDQVLHED ET TNRMHES LMLFDSICNN KFFIDTSIIL FLNKKDLFGE KIKKSPLTIC FPEYTGPNTY EDAAAYIQAQ FESKNRSPNK EIY CHMTCA TDTNNIQVVF DAVTDIIIAN NLRGCGLY |
-Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Macromolecule | Name: 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 |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 38.402867 KDa |
Recombinant expression | Organism: Trichoplusia ni (cabbage looper) |
Sequence | String: HHHHHHGSSG SELDQLRQEA EQLKNQIRDA RKACADATLS QITNNIDPVG RIQMRTRRTL RGHLAKIYAM HWGTDSRLLV SASQDGKLI IWDSYTTNKV HAIPLRSSWV MTCAYAPSGN YVACGGLDNI CSIYNLKTRE GNVRVSRELA GHTGYLSCCR F LDDNQIVT ...String: HHHHHHGSSG SELDQLRQEA EQLKNQIRDA RKACADATLS QITNNIDPVG RIQMRTRRTL RGHLAKIYAM HWGTDSRLLV SASQDGKLI IWDSYTTNKV HAIPLRSSWV MTCAYAPSGN YVACGGLDNI CSIYNLKTRE GNVRVSRELA GHTGYLSCCR F LDDNQIVT SSGDTTCALW DIETGQQTTT FTGHTGDVMS LSLAPDTRLF VSGACDASAK LWDVREGMCR QTFTGHESDI NA ICFFPNG NAFATGSDDA TCRLFDLRAD QELMTYSHDN IICGITSVSF SKSGRLLLAG YDDFNCNVWD ALKADRAGVL AGH DNRVSC LGVTDDGMAV ATGSWDSFLK IWN |
-Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 7.861143 KDa |
Recombinant expression | Organism: Trichoplusia ni (cabbage looper) |
Sequence | String: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L |
-Macromolecule #4: scFv16
Macromolecule | Name: scFv16 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Mus musculus (house mouse) |
Molecular weight | Theoretical: 32.898781 KDa |
Recombinant expression | Organism: Trichoplusia ni (cabbage looper) |
Sequence | String: MLLVNQSHQG FNKEHTSKMV SAIVLYVLLA AAAHSAFADV QLVESGGGLV QPGGSRKLSC SASGFAFSSF GMHWVRQAPE KGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSEDT AMYYCVRSIY YYGSSPFDFW GQGTTLTVSS G GGGSGGGG ...String: MLLVNQSHQG FNKEHTSKMV SAIVLYVLLA AAAHSAFADV QLVESGGGLV QPGGSRKLSC SASGFAFSSF GMHWVRQAPE KGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSEDT AMYYCVRSIY YYGSSPFDFW GQGTTLTVSS G GGGSGGGG SGGGGSDIVM TQATSSVPVT PGESVSISCR SSKSLLHSNG NTYLYWFLQR PGQSPQLLIY RMSNLASGVP DR FSGSGSG TAFTLTISRL EAEDVGVYYC MQHLEYPLTF GAGTKLELKG SLEVLFQGPA AAHHHHHHHH |
-Macromolecule #5: Alpha-2A adrenergic receptor
Macromolecule | Name: Alpha-2A adrenergic receptor / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 50.704566 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MFRQEQPLAE GSFAPMGSLQ PDAGNASWNG TEAPGGGARA TPYSLQVTLT LVCLAGLLML LTVFGNVLVI IAVFTSRALK APQNLFLVS LASADILVAT LVIPFSLANE VMGYWYFGKA WCEIYLALDV LFCTSSIVHL CAISLDRYWS ITQAIEYNLK R TPRRIKAI ...String: MFRQEQPLAE GSFAPMGSLQ PDAGNASWNG TEAPGGGARA TPYSLQVTLT LVCLAGLLML LTVFGNVLVI IAVFTSRALK APQNLFLVS LASADILVAT LVIPFSLANE VMGYWYFGKA WCEIYLALDV LFCTSSIVHL CAISLDRYWS ITQAIEYNLK R TPRRIKAI IITVWVISAV ISFPPLISIE KKGGGGGPQP AEPRCEINDQ KWYVISSCIG SFFAPCLIMI LVYVRIYQIA KR RTRVPPS RRGPDAVAAP PGGTERRPNG LGPERSAGPG GAEAEPLPTQ LNGAPGEPAP AGPRDTDALD LEESSSSDHA ERP PGPRRP ERGPRGKGKA RASQVKPGDS LPRRGPGATG IGTPAAGPGE ERVGAAKASR WRGRQNREKR FTFVLAVVIG VFVV CWFPF FFTYTLTAVG CSVPRTLFKF FFWFGYCNSS LNPVIYTIFN HDFRRAFKKI LCRGDRKRIV |
-Macromolecule #6: Noradrenaline
Macromolecule | Name: Noradrenaline / type: ligand / ID: 6 / Number of copies: 1 / Formula: E5E |
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Molecular weight | Theoretical: 170.186 Da |
Chemical component information | ChemComp-E5E: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Sugar embedding | Material: vitreous ice |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 56.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Calibrated defocus max: 2.0 µm / Calibrated defocus min: 0.8 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.4000000000000001 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 105000 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 261073 |
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Initial angle assignment | Type: RANDOM ASSIGNMENT |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |