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- EMDB-36404: Fenoldopam-bound hTAAR1-Gs protein complex -

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Basic information

Entry
Database: EMDB / ID: EMD-36404
TitleFenoldopam-bound hTAAR1-Gs protein complex
Map data
Sample
  • Complex: hTAAR1-bound T1AM in complex with Gs heterotrimer
    • Complex: Gs heterotrimer
      • Protein or peptide: mGs
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Complex: scFV16
      • Protein or peptide: ScFv16
    • Complex: T1AM-bound hTAAR1
      • Protein or peptide: Soluble cytochrome b562,Trace amine-associated receptor 1
  • Ligand: (1R)-6-chloranyl-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol
KeywordsComplex / Agonist / MEMBRANE PROTEIN / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


Amine ligand-binding receptors / trace-amine receptor activity / endomembrane system / electron transport chain / G protein-coupled receptor activity / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors ...Amine ligand-binding receptors / trace-amine receptor activity / endomembrane system / electron transport chain / G protein-coupled receptor activity / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / 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 / 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / 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) / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / Ca2+ pathway / retina development in camera-type eye / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / electron transfer activity / periplasmic space / G protein-coupled receptor signaling pathway / iron ion binding / lysosomal membrane / GTPase activity / heme binding / synapse / endoplasmic reticulum membrane / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Trace amine associated receptor 1 / Trace amine associated receptor family / : / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain ...Trace amine associated receptor 1 / Trace amine associated receptor family / : / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Serpentine type 7TM GPCR chemoreceptor Srsx / 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 / 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. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
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 / Trace amine-associated receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.84 Å
AuthorsXu Z / Guo LL / Zhao C / Shen SY / Sun JP / Shao ZH
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31972916 China
CitationJournal: Nature / Year: 2023
Title: Ligand recognition and G-protein coupling of trace amine receptor TAAR1.
Authors: Zheng Xu / Lulu Guo / Jingjing Yu / Siyuan Shen / Chao Wu / Weifeng Zhang / Chang Zhao / Yue Deng / Xiaowen Tian / Yuying Feng / Hanlin Hou / Lantian Su / Hongshuang Wang / Shuo Guo / Heli ...Authors: Zheng Xu / Lulu Guo / Jingjing Yu / Siyuan Shen / Chao Wu / Weifeng Zhang / Chang Zhao / Yue Deng / Xiaowen Tian / Yuying Feng / Hanlin Hou / Lantian Su / Hongshuang Wang / Shuo Guo / Heli Wang / Kexin Wang / Peipei Chen / Jie Zhao / Xiaoyu Zhang / Xihao Yong / Lin Cheng / Lunxu Liu / Shengyong Yang / Fan Yang / Xiaohui Wang / Xiao Yu / Yunfei Xu / Jin-Peng Sun / Wei Yan / Zhenhua Shao /
Abstract: Trace-amine-associated receptors (TAARs), a group of biogenic amine receptors, have essential roles in neurological and metabolic homeostasis. They recognize diverse endogenous trace amines and ...Trace-amine-associated receptors (TAARs), a group of biogenic amine receptors, have essential roles in neurological and metabolic homeostasis. They recognize diverse endogenous trace amines and subsequently activate a range of G-protein-subtype signalling pathways. Notably, TAAR1 has emerged as a promising therapeutic target for treating psychiatric disorders. However, the molecular mechanisms underlying its ability to recognize different ligands remain largely unclear. Here we present nine cryo-electron microscopy structures, with eight showing human and mouse TAAR1 in a complex with an array of ligands, including the endogenous 3-iodothyronamine, two antipsychotic agents, the psychoactive drug amphetamine and two identified catecholamine agonists, and one showing 5-HTR in a complex with an antipsychotic agent. These structures reveal a rigid consensus binding motif in TAAR1 that binds to endogenous trace amine stimuli and two extended binding pockets that accommodate diverse chemotypes. Combined with mutational analysis, functional assays and molecular dynamic simulations, we elucidate the structural basis of drug polypharmacology and identify the species-specific differences between human and mouse TAAR1. Our study provides insights into the mechanism of ligand recognition and G-protein selectivity by TAAR1, which may help in the discovery of ligands or therapeutic strategies for neurological and metabolic disorders.
History
DepositionJun 2, 2023-
Header (metadata) releaseNov 15, 2023-
Map releaseNov 15, 2023-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_36404.png

Downloads & links

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Map

FileDownload / File: emd_36404.map.gz / Format: CCP4 / Size: 34.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
1.04 Å/pix.
x 208 pix.
= 216.32 Å		1.04 Å/pix.
x 208 pix.
= 216.32 Å		1.04 Å/pix.
x 208 pix.
= 216.32 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.04 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.4
Minimum - Maximum-4.4645967 - 5.643005
Average (Standard dev.)-0.0061627086 (±0.12055482)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions208208208
Spacing208208208
CellA=B=C: 216.31999 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_36404_half_map_1.map
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Half map: #1

Fileemd_36404_half_map_2.map
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Sample components

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Entire : hTAAR1-bound T1AM in complex with Gs heterotrimer

EntireName: hTAAR1-bound T1AM in complex with Gs heterotrimer
Components
  • Complex: hTAAR1-bound T1AM in complex with Gs heterotrimer
    • Complex: Gs heterotrimer
      • Protein or peptide: mGs
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Complex: scFV16
      • Protein or peptide: ScFv16
    • Complex: T1AM-bound hTAAR1
      • Protein or peptide: Soluble cytochrome b562,Trace amine-associated receptor 1
  • Ligand: (1R)-6-chloranyl-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol

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Supramolecule #1: hTAAR1-bound T1AM in complex with Gs heterotrimer

SupramoleculeName: hTAAR1-bound T1AM in complex with Gs heterotrimer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5

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Supramolecule #2: Gs heterotrimer

SupramoleculeName: Gs heterotrimer / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2, #5
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: scFV16

SupramoleculeName: scFV16 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #4
Source (natural)Organism: Mus musculus (house mouse)

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Supramolecule #4: T1AM-bound hTAAR1

SupramoleculeName: T1AM-bound hTAAR1 / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: mGs

MacromoleculeName: mGs / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 43.117918 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGCTLRNEEK AQREANKKIE KQLQKDKQVY RATHRLLLLG AGESGKNTIV KQMRIYHVNG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String:
MGCTLRNEEK AQREANKKIE KQLQKDKQVY RATHRLLLLG AGESGKNTIV KQMRIYHVNG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTSGIFETK FQVDKVNFHM FDVGAQRDER RKWIQCFNDV TAIIFVVASS SYNMVIREDN QT NRLQAAL KLFDSIWNNK WLRDTSVILF LNKQDLLAEK VLAGKSKIED YFPEFARYTT PEDATPEPGE DPRVTRAKYF IRD EFLRIS TASGDGRHYC YPHFTCSVDT ENIRRVFNDC RDIIQRMHLR QYELL

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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: Soluble cytochrome b562,Trace amine-associated receptor 1

MacromoleculeName: Soluble cytochrome b562,Trace amine-associated receptor 1
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 54.128133 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DYKDDDDKHH HHHHHHHHEN LYFQGADLED NWETLNDNLK VIEKADNAAQ VKDALTKMRA AALDAQKATP PKLEDKSPDS PEMKDFRHG FDILVGQIDD ALKLANEGKV KEAQAAAEQL KTTRNAYIQK YLMMPFCHNI INISCVKNNW SNDVRASLYS L MVLIILTT ...String:
DYKDDDDKHH HHHHHHHHEN LYFQGADLED NWETLNDNLK VIEKADNAAQ VKDALTKMRA AALDAQKATP PKLEDKSPDS PEMKDFRHG FDILVGQIDD ALKLANEGKV KEAQAAAEQL KTTRNAYIQK YLMMPFCHNI INISCVKNNW SNDVRASLYS L MVLIILTT LVGNLIVIVS ISHFKQLHTP TNWLIHSMAT VDFLLGCLVM PYSMVRSAEH CWYFGEVFCK IHTSTDIMLS SA SIFHLSF ISIDRYYAVC DPLRYKAKMN ILVICVMIFI SWSVPAVFAF GMIFLELNFK GAEEIYYKHV HCRGGCSVFF SKI SGVLTF MTSFYIPGSI MLCVYYRIYL IAKEQARLIS DANQKLQIGL EMKNGISQSK ERKAVKTLGI VMGVFLICWC PFFI CTVMD PFLHYIIPPT LNDVLIWFGY LNSTFNPMVY AFFYPWFRKA LKMMLFGKIF QKDSSRCKLF LELSS

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

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Macromolecule #4: ScFv16

MacromoleculeName: ScFv16 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 26.709748 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGSSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...String:
DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGSSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL KAAA

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Macromolecule #5: 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: 5 / 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 #6: (1R)-6-chloranyl-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benz...

MacromoleculeName: (1R)-6-chloranyl-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol
type: ligand / ID: 6 / Number of copies: 1 / Formula: G3C
Molecular weightTheoretical: 305.756 Da
Chemical component information

ChemComp-G3C:
(1R)-6-chloranyl-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol

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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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.84 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 475535
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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