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- EMDB-42268: Cryo-EM Structure of the Ro5256390-bound hTA1-Gs heterotrimer sig... -

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Entry
Database: EMDB / ID: EMD-42268
TitleCryo-EM Structure of the Ro5256390-bound hTA1-Gs heterotrimer signaling complex
Map dataPrimary Map
Sample
  • Complex: hTA1-Gs-Nb35 complex (Ro5256390)
    • Protein or peptide: Soluble cytochrome b562,Beta-2 adrenergic receptor,Trace amine-associated receptor 1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Nanobody 35Single-domain antibody
  • Ligand: (2R,4S)-4-[(2S)-2-phenylbutyl]-1,3-oxazolidin-2-amine
KeywordsGPCR / Signaling Complex / Trace Amine-associated Receptor / MEMBRANE PROTEIN
Function / homology
Function and homology information


adenylate cyclase regulator activity / regulation of parathyroid hormone secretion / COPI-coated Golgi to ER transport vesicle / post-embryonic body morphogenesis / Amine ligand-binding receptors / response to parathyroid hormone / trace-amine receptor activity / sensory perception of chemical stimulus / genomic imprinting / mu-type opioid receptor binding ...adenylate cyclase regulator activity / regulation of parathyroid hormone secretion / COPI-coated Golgi to ER transport vesicle / post-embryonic body morphogenesis / Amine ligand-binding receptors / response to parathyroid hormone / trace-amine receptor activity / sensory perception of chemical stimulus / genomic imprinting / mu-type opioid receptor binding / tissue homeostasis / corticotropin-releasing hormone receptor 1 binding / energy reserve metabolic process / positive regulation of sodium ion transport / endochondral ossification / embryonic cranial skeleton morphogenesis / positive regulation of osteoclast differentiation / desensitization of G protein-coupled receptor signaling pathway by arrestin / beta2-adrenergic receptor activity / norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure / embryonic hindlimb morphogenesis / positive regulation of mini excitatory postsynaptic potential / alkylglycerophosphoethanolamine phosphodiesterase activity / positive regulation of cAMP-dependent protein kinase activity / cartilage development / norepinephrine binding / Adrenoceptors / heat generation / positive regulation of autophagosome maturation / positive regulation of AMPA receptor activity / activation of transmembrane receptor protein tyrosine kinase activity / beta-2 adrenergic receptor binding / negative regulation of smooth muscle contraction / positive regulation of lipophagy / skin development / response to psychosocial stress / negative regulation of multicellular organism growth / : / endosome to lysosome transport / adrenergic receptor signaling pathway / diet induced thermogenesis / cellular response to glucagon stimulus / neuronal dense core vesicle / positive regulation of protein kinase A signaling / alpha-tubulin binding / hair follicle placode formation / adenylate cyclase binding / smooth muscle contraction / developmental growth / D1 dopamine receptor binding / G-protein alpha-subunit binding / potassium channel regulator activity / regulation of signal transduction / positive regulation of osteoblast differentiation / positive regulation of bone mineralization / positive regulation of cAMP-mediated signaling / adenylate cyclase-activating adrenergic receptor signaling pathway / brown fat cell differentiation / regulation of sodium ion transport / bone resorption / ruffle / ionotropic glutamate receptor binding / insulin-like growth factor receptor binding / activation of adenylate cyclase activity / adenylate cyclase activator activity / negative regulation of blood pressure / response to cold / receptor-mediated endocytosis / post-embryonic development / G protein activity / trans-Golgi network membrane / skeletal system development / G protein-coupled receptor activity / Olfactory Signaling Pathway / G-protein beta/gamma-subunit complex binding / clathrin-coated endocytic vesicle membrane / Activation of the phototransduction cascade / multicellular organism growth / 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 / bone development / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / positive regulation of protein serine/threonine kinase activity / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of insulin secretion / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / recycling endosome / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion
Similarity search - Function
Trace amine associated receptor 1 / Trace amine associated receptor family / Beta 2 adrenoceptor / Adrenoceptor family / Cytochrome b562 / Cytochrome b562 / G-protein alpha subunit, group S / Cytochrome c/b562 / Serpentine type 7TM GPCR chemoreceptor Srsx / G-alpha domain profile. ...Trace amine associated receptor 1 / Trace amine associated receptor family / Beta 2 adrenoceptor / Adrenoceptor family / Cytochrome b562 / Cytochrome b562 / G-protein alpha subunit, group S / Cytochrome c/b562 / 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
Beta-2 adrenergic receptor / Soluble cytochrome b562 / 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 / Trace amine-associated receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human) / Rattus norvegicus (Norway rat) / Lama glama (llama)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.35 Å
AuthorsZilberg G / Warren AL / Parpounas AK / Wacker D
Funding support United States, 4 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM133504 United States
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)MH132317 United States
National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA)DA053558 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM062754 United States
CitationJournal: Nat Commun / Year: 2024
Title: Molecular basis of human trace amine-associated receptor 1 activation.
Authors: Gregory Zilberg / Alexandra K Parpounas / Audrey L Warren / Shifan Yang / Daniel Wacker /
Abstract: The human trace amine-associated receptor 1 (hTAAR1, hTA1) is a key regulator of monoaminergic neurotransmission and the actions of psychostimulants. Despite preclinical research demonstrating its ...The human trace amine-associated receptor 1 (hTAAR1, hTA1) is a key regulator of monoaminergic neurotransmission and the actions of psychostimulants. Despite preclinical research demonstrating its tractability as a drug target, its molecular mechanisms of activation remain unclear. Moreover, poorly understood pharmacological differences between rodent and human TA1 complicate the translation of findings from preclinical disease models into novel pharmacotherapies. To elucidate hTA1's mechanisms on the molecular scale and investigate the underpinnings of its divergent pharmacology from rodent orthologs, we herein report the structure of the human TA1 receptor in complex with a Gαs heterotrimer. Our structure reveals shared structural elements with other TAARs, as well as with its closest monoaminergic orthologue, the serotonin receptor 5-HT4R. We further find that a single mutation dramatically shifts the selectivity of hTA1 towards that of its rodent orthologues, and report on the effects of substituting residues to those found in serotonin and dopamine receptors. Strikingly, we also discover that the atypical antipsychotic medication and pan-monoaminergic antagonist asenapine potently and efficaciously activates hTA1. Together our studies provide detailed insight into hTA1 structure and function, contrast its molecular pharmacology with that of related receptors, and uncover off-target activities of monoaminergic drugs at hTA1.
History
DepositionOct 8, 2023-
Header (metadata) releaseJan 10, 2024-
Map releaseJan 10, 2024-
UpdateMay 1, 2024-
Current statusMay 1, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_42268.png

Downloads & links

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Map

FileDownload / File: emd_42268.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationPrimary Map
Voxel sizeX=Y=Z: 1.069 Å
Density
Contour LevelBy AUTHOR: 0.26
Minimum - Maximum-0.50927114 - 1.1582791
Average (Standard dev.)0.00025221467 (±0.037575398)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 273.664 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map 1

Fileemd_42268_half_map_1.map
AnnotationHalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 2

Fileemd_42268_half_map_2.map
AnnotationHalf map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : hTA1-Gs-Nb35 complex (Ro5256390)

EntireName: hTA1-Gs-Nb35 complex (Ro5256390)
Components
  • Complex: hTA1-Gs-Nb35 complex (Ro5256390)
    • Protein or peptide: Soluble cytochrome b562,Beta-2 adrenergic receptor,Trace amine-associated receptor 1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Nanobody 35Single-domain antibody
  • Ligand: (2R,4S)-4-[(2S)-2-phenylbutyl]-1,3-oxazolidin-2-amine

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Supramolecule #1: hTA1-Gs-Nb35 complex (Ro5256390)

SupramoleculeName: hTA1-Gs-Nb35 complex (Ro5256390) / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Soluble cytochrome b562,Beta-2 adrenergic receptor,Trace amine-as...

MacromoleculeName: Soluble cytochrome b562,Beta-2 adrenergic receptor,Trace amine-associated receptor 1
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 60.019816 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKTIIALSYI FCLVFADYKD DDDAKLQTMH HHHHHHHHHE NLYFQGGTTA DLEDNWETLN DNLKVIEKAD NAAQVKDALT KMRAAALDA QKATPPKLED KSPDSPEMKD FRHGFDILVG QIDDALKLAN EGKVKEAQAA AEQLKTTRNA YIQKYLMGQP G NGSAFLLA ...String:
MKTIIALSYI FCLVFADYKD DDDAKLQTMH HHHHHHHHHE NLYFQGGTTA DLEDNWETLN DNLKVIEKAD NAAQVKDALT KMRAAALDA QKATPPKLED KSPDSPEMKD FRHGFDILVG QIDDALKLAN EGKVKEAQAA AEQLKTTRNA YIQKYLMGQP G NGSAFLLA PNRSHAPDHD VTQQRDEMMP FCHNIINISC VKNNWSNDVR ASLYSLMVLI ILTTLVGNLI VIVSISHFKQ LH TPTNWLI HSMATVDFLL GCLVMPYSMV RSAEHCWYFG EVFCKIHTST DIMLSSASIW HLSFISIDRY YAVCDPLRYK AKM NILVIC VMIFISWSVP AVFAFGMIFL ELNFKGAEEI YYKHVHCRGG CSVFFSKISG VLTFMTSFYI PGSIMLCVYY RIYL IAKEQ ARLISDANQK LQIGLEMKNG ISQSKERKAV KTLGIVMGVF LICWCPFFIC TVMDPFLHYI IPPTLNDVLI WFGYL NSTF NPMVYAFFYP WFRKALKMML FGKIFQKDSS RCKLFLELSS

UniProtKB: Soluble cytochrome b562, Beta-2 adrenergic receptor, Trace amine-associated receptor 1

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Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: 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
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.418086 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MHHHHHHLEV LFQGPGSSGS ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLV SASQDGKLII WDSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG H TGYLSCCR ...String:
MHHHHHHLEV LFQGPGSSGS ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLV SASQDGKLII WDSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG H TGYLSCCR FLDDNQIVTS SGDTTCALWD IETGQQTTTF TGHTGDVMSL SLAPDTRLFV SGACDASAKL WDVREGMCRQ TF TGHESDI NAICFFPNGN AFATGSDDAT CRLFDLRADQ ELMTYSHDNI ICGITSVSFS KSGRLLLAGY DDFNCNVWDA LKA DRAGVL AGHDNRVSCL GVTDDGMAVA TGSWDSFLKI WN

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #3: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short

MacromoleculeName: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 45.803598 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKSTIVKQM RILHVNGFNG EGGEEDPQAA RSNSDGEKA TKVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPN FDFPPEFYEH AKALWEDEGV R ACYERSNE ...String:
MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKSTIVKQM RILHVNGFNG EGGEEDPQAA RSNSDGEKA TKVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPN FDFPPEFYEH AKALWEDEGV R ACYERSNE YQLIDCAQYF LDKIDVIKQA EYMPTEQDLL RCRVLTSGIF ETKFQVDKVN FHMFDVGAQR DERRKWIQCF ND VTAIIFV VASSSYNMVI REDNQTNRLQ EALKLFDSIW NNKWLRDTSV ILFLNKQDLL AEKVLAGKSK IEDYFPEFAR YTT PEDATP EPGEDPRVTR AKYFIRDEFL RISTASGDGR HYCYPHFTCS VDTENIRRVF NDCRDIIQRM HLRQYELL

UniProtKB: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short

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Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Macromolecule #5: Nanobody 35

MacromoleculeName: Nanobody 35 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama)
Molecular weightTheoretical: 14.71432 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
QVQLQESGGG LVQPGGSLRL SCAASGFTFS NYKMNWVRQA PGKGLEWVSD ISQSGASISY TGSVKGRFTI SRDNAKNTLY LQMNSLKPE DTAVYYCARC PAPFTRDCFD VTSTTYAYRG QGTQVTVSSH HHHHH

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Macromolecule #6: (2R,4S)-4-[(2S)-2-phenylbutyl]-1,3-oxazolidin-2-amine

MacromoleculeName: (2R,4S)-4-[(2S)-2-phenylbutyl]-1,3-oxazolidin-2-amine / type: ligand / ID: 6 / Number of copies: 1 / Formula: WV8
Molecular weightTheoretical: 218.295 Da
Chemical component information

ChemComp-WV8:
(2R,4S)-4-[(2S)-2-phenylbutyl]-1,3-oxazolidin-2-amine

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1.2 mg/mL
BufferpH: 7.4
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300
VitrificationCryogen name: ETHANE / Instrument: LEICA EM GP

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.5 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 53.88 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7xt8

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: ANGULAR RECONSTITUTION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.35 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 626370

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