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- EMDB-37438: Cryo-EM structure of the CHA-bound mTAAR1 complex -

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Basic information

Entry
Database: EMDB / ID: EMD-37438
TitleCryo-EM structure of the CHA-bound mTAAR1 complex
Map data
Sample
  • Complex: Cryo-EM structure of the CHA-bound mTAAR1 complex
    • Protein or peptide: Trace amine-associated receptor 1
  • Ligand: CYCLOHEXYLAMMONIUM ION
KeywordsCHA / mTAAR1 / MEMBRANE PROTEIN
Function / homology
Function and homology information


G protein-coupled amine receptor activity / Amine ligand-binding receptors / trace-amine receptor activity / G alpha (s) signalling events / positive regulation of cAMP-mediated signaling / adenylate cyclase-activating dopamine receptor signaling pathway / G protein-coupled receptor signaling pathway / membrane / plasma membrane
Similarity search - Function
Trace amine associated receptor 1 / Trace amine associated receptor family / Serpentine type 7TM GPCR chemoreceptor Srsx / 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)
Similarity search - Domain/homology
Trace amine-associated receptor 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.04 Å
AuthorsRong NK / Guo LL / Zhang MH / Li Q / Yang F / Sun JP
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81773704 China
CitationJournal: Cell / Year: 2023
Title: Structural and signaling mechanisms of TAAR1 enabled preferential agonist design.
Authors: Pan Shang / Naikang Rong / Jing-Jing Jiang / Jie Cheng / Ming-Hui Zhang / Dongwei Kang / Lei Qi / Lulu Guo / Gong-Ming Yang / Qun Liu / Zhenzhen Zhou / Xiao-Bing Li / Kong-Kai Zhu / Qing- ...Authors: Pan Shang / Naikang Rong / Jing-Jing Jiang / Jie Cheng / Ming-Hui Zhang / Dongwei Kang / Lei Qi / Lulu Guo / Gong-Ming Yang / Qun Liu / Zhenzhen Zhou / Xiao-Bing Li / Kong-Kai Zhu / Qing-Biao Meng / Xiang Han / Wenqi Yan / Yalei Kong / Lejin Yang / Xiaohui Wang / Dapeng Lei / Xin Feng / Xinyong Liu / Xiao Yu / Yue Wang / Qian Li / Zhen-Hua Shao / Fan Yang / Jin-Peng Sun /
Abstract: Trace amine-associated receptor 1 (TAAR1) senses a spectrum of endogenous amine-containing metabolites (EAMs) to mediate diverse psychological functions and is useful for schizophrenia treatment ...Trace amine-associated receptor 1 (TAAR1) senses a spectrum of endogenous amine-containing metabolites (EAMs) to mediate diverse psychological functions and is useful for schizophrenia treatment without the side effects of catalepsy. Here, we systematically profiled the signaling properties of TAAR1 activation and present nine structures of TAAR1-Gs/Gq in complex with EAMs, clinical drugs, and synthetic compounds. These structures not only revealed the primary amine recognition pocket (PARP) harboring the conserved acidic D for conserved amine recognition and "twin" toggle switch for receptor activation but also elucidated that targeting specific residues in the second binding pocket (SBP) allowed modulation of signaling preference. In addition to traditional drug-induced Gs signaling, Gq activation by EAM or synthetic compounds is beneficial to schizophrenia treatment. Our results provided a structural and signaling framework for molecular recognition by TAAR1, which afforded structural templates and signal clues for TAAR1-targeted candidate compounds design.
History
DepositionSep 11, 2023-
Header (metadata) releaseDec 27, 2023-
Map releaseDec 27, 2023-
UpdateDec 27, 2023-
Current statusDec 27, 2023Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_37438.png

Downloads & links

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Map

FileDownload / File: emd_37438.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.92 Å
Density
Contour LevelBy AUTHOR: 0.187
Minimum - Maximum-0.0074279225 - 1.7451571
Average (Standard dev.)-0.001273287 (±0.018789561)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 235.52 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_37438_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_37438_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Cryo-EM structure of the CHA-bound mTAAR1 complex

EntireName: Cryo-EM structure of the CHA-bound mTAAR1 complex
Components
  • Complex: Cryo-EM structure of the CHA-bound mTAAR1 complex
    • Protein or peptide: Trace amine-associated receptor 1
  • Ligand: CYCLOHEXYLAMMONIUM ION

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Supramolecule #1: Cryo-EM structure of the CHA-bound mTAAR1 complex

SupramoleculeName: Cryo-EM structure of the CHA-bound mTAAR1 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Trace amine-associated receptor 1

MacromoleculeName: Trace amine-associated receptor 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 37.656586 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MHLCHAITNI SHRNSDWSRE VQASLYSLMS LIILATLVGN LIVIISISHF KQLHTPTNWL LHSMAIVDFL LGCLIMPCSM VRTVERCWY FGEILCKVHT STDIMLSSAS IFHLAFISID RYCAVCDPLR YKAKINISTI LVMILVSWSL PAVYAFGMIF L ELNLKGVE ...String:
MHLCHAITNI SHRNSDWSRE VQASLYSLMS LIILATLVGN LIVIISISHF KQLHTPTNWL LHSMAIVDFL LGCLIMPCSM VRTVERCWY FGEILCKVHT STDIMLSSAS IFHLAFISID RYCAVCDPLR YKAKINISTI LVMILVSWSL PAVYAFGMIF L ELNLKGVE ELYRSQVSDL GGCSPFFSKV SGVLAFMTSF YIPGSVMLFV YYRIYFIAKG QARSINRTNV QVGLEGKSQA PQ SKETKAA KTLGIMVGVF LVCWCPFFLC TVLDPFLGYV IPPSLNDALY WFGYLNSALN PMVYAFFYPW FRRALKMVLL GKI FQKDSS RSKLFL

UniProtKB: Trace amine-associated receptor 1

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Macromolecule #2: CYCLOHEXYLAMMONIUM ION

MacromoleculeName: CYCLOHEXYLAMMONIUM ION / type: ligand / ID: 2 / Number of copies: 1 / Formula: HAI
Molecular weightTheoretical: 100.182 Da
Chemical component information

ChemComp-HAI:
CYCLOHEXYLAMMONIUM ION

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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: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 1.875 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: DIFFRACTION / Nominal defocus max: 2.0 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: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.04 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 296951
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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