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- EMDB-61567: Cryo-EM structure of the METH-bound hTAAR1-Gs complex -

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Entry
Database: EMDB / ID: EMD-61567
TitleCryo-EM structure of the METH-bound hTAAR1-Gs complex
Map data
Sample
  • Complex: METH-bound hTAAR1-Gs complex
    • 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(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Nb35
    • Protein or peptide: Soluble cytochrome b562,Trace amine-associated receptor 1
  • Ligand: (2S)-N-methyl-1-phenylpropan-2-amine
Keywordscryo-EM / GPCR / Trace amine-associated receptor 1 / SIGNALING PROTEIN
Function / homology
Function and homology information


Amine ligand-binding receptors / trace-amine receptor activity / PKA activation in glucagon signalling / hair follicle placode formation / developmental growth / D1 dopamine receptor binding / intracellular transport / vascular endothelial cell response to laminar fluid shear stress / renal water homeostasis / Hedgehog 'off' state ...Amine ligand-binding receptors / trace-amine receptor activity / PKA activation in glucagon signalling / hair follicle placode formation / developmental growth / D1 dopamine receptor binding / intracellular transport / vascular endothelial cell response to laminar fluid shear stress / renal water homeostasis / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / endomembrane system / regulation of insulin secretion / cellular response to glucagon stimulus / adenylate cyclase activator activity / trans-Golgi network membrane / negative regulation of inflammatory response to antigenic stimulus / electron transport chain / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / G protein-coupled receptor activity / bone development / G-protein beta/gamma-subunit complex binding / platelet aggregation / Olfactory Signaling Pathway / cognition / 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 / adenylate cyclase-activating G protein-coupled 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 / 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 / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / sensory perception of smell / 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) / positive regulation of cold-induced thermogenesis / G protein activity / 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 / G alpha (i) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Ras protein signal transduction / periplasmic space / electron transfer activity / Extra-nuclear estrogen signaling / cell population proliferation / G protein-coupled receptor signaling pathway / iron ion binding / lysosomal membrane / GTPase activity / synapse / heme binding / endoplasmic reticulum membrane / protein-containing complex binding / GTP binding / signal transduction / extracellular exosome / metal ion binding / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Trace amine associated receptor 1 / Trace amine associated receptor family / : / G-protein alpha subunit, group S / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Serpentine type 7TM GPCR chemoreceptor Srsx / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion ...Trace amine associated receptor 1 / Trace amine associated receptor family / : / G-protein alpha subunit, group S / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Serpentine type 7TM GPCR chemoreceptor Srsx / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / 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. / WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
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 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Trace amine-associated receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.66 Å
AuthorsLin Y / Wang J / Shi F
Funding support China, 7 items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2020YFA0908500 China
Ministry of Science and Technology (MoST, China)2020YFA0908400 China
Ministry of Science and Technology (MoST, China)2018YFA0508100 China
National Natural Science Foundation of China (NSFC)31971127 China
National Natural Science Foundation of China (NSFC)31900895 China
National Natural Science Foundation of China (NSFC)32000851 China
National Natural Science Foundation of China (NSFC)31900930 China
CitationJournal: J Med Chem / Year: 2024
Title: Molecular Mechanisms of Methamphetamine-Induced Addiction via TAAR1 Activation.
Authors: Yun Lin / Jiening Wang / Fan Shi / Linlin Yang / Shan Wu / Anna Qiao / Sheng Ye /
Abstract: Trace amine-associated receptor 1 (TAAR1), a member of the trace amine receptor family, recognizes various trace amines in the brain, including endogenous β-phenylethylamine (PEA) and ...Trace amine-associated receptor 1 (TAAR1), a member of the trace amine receptor family, recognizes various trace amines in the brain, including endogenous β-phenylethylamine (PEA) and methamphetamine (METH). TAAR1 is a novel target for several neurological disorders, including schizophrenia, depression, and substance abuse. Herein, we report the structure of the human TAAR1-G protein complex bound to METH. Using functional studies, we reveal the molecular basis of METH recognition by TAAR1, and potential mechanisms underlying the selectivity of TAAR1 for different ligands. Molecular dynamics simulations further elucidated possible mechanisms for the binding of chiral amphetamine (AMPH)-like psychoactive drugs to TAAR1. Additionally, we discovered a hydrophobic core on the transmembrane helices (TM), TM5 and TM6, explaining the unique mechanism of TAAR1 activation. These findings reveal the ligand recognition pattern and activation mechanism of TAAR1, which has important implications for the development of next-generation treatments for substance abuse and various neurological disorders.
History
DepositionSep 16, 2024-
Header (metadata) releaseOct 16, 2024-
Map releaseOct 16, 2024-
UpdateNov 20, 2024-
Current statusNov 20, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_61567.png

Downloads & links

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Map

FileDownload / File: emd_61567.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 320 pix.
= 272.32 Å		0.85 Å/pix.
x 320 pix.
= 272.32 Å		0.85 Å/pix.
x 320 pix.
= 272.32 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.851 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.734
Minimum - Maximum-3.0488634 - 5.1424537
Average (Standard dev.)-0.0017813309 (±0.078212634)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 272.32 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_61567_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_61567_half_map_2.map
Projections & Slices
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Sample components

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Entire : METH-bound hTAAR1-Gs complex

EntireName: METH-bound hTAAR1-Gs complex
Components
  • Complex: METH-bound hTAAR1-Gs complex
    • 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(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Nb35
    • Protein or peptide: Soluble cytochrome b562,Trace amine-associated receptor 1
  • Ligand: (2S)-N-methyl-1-phenylpropan-2-amine

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Supramolecule #1: METH-bound hTAAR1-Gs complex

SupramoleculeName: METH-bound hTAAR1-Gs complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: 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: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 45.683434 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKNTIVKQM RILHVNGFNG EGGEEDPQAA RSNSDGEKA TKVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPD FDFPPEFYEH AKALWEDEGV R ACYERSNE ...String:
MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKNTIVKQM RILHVNGFNG EGGEEDPQAA RSNSDGEKA TKVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPD FDFPPEFYEH AKALWEDEGV R ACYERSNE YQLIDCAQYF LDKIDVIKQA DYVPSDQDLL RCRVLTSGIF ETKFQVDKVN FHMFDVGAQR DERRKWIQCF ND VTAIIFV VASSSYNMVI REDNQTNRLQ AALKLFDSIW NNKWLRDTSV ILFLNKQDLL AEKVLAGKSK IEDYFPEFAR YTT PEDATP EPGEDPRVTR AKYFIRDEFL RISTASGDGR HYCYPHFTCA VDTENIRRVF NDCRDIIQRM HLRQYELL

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

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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: 38.744371 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MHHHHHHGSL LQSELDQLRQ EAEQLKNQIR DARKACADAT LSQITNNIDP VGRIQMRTRR TLRGHLAKIY AMHWGTDSRL LVSASQDGK LIIWDSYTTN KVHAIPLRSS WVMTCAYAPS GNYVACGGLD NICSIYNLKT REGNVRVSRE LAGHTGYLSC C RFLDDNQI ...String:
MHHHHHHGSL LQSELDQLRQ EAEQLKNQIR DARKACADAT LSQITNNIDP VGRIQMRTRR TLRGHLAKIY AMHWGTDSRL LVSASQDGK LIIWDSYTTN KVHAIPLRSS WVMTCAYAPS GNYVACGGLD NICSIYNLKT REGNVRVSRE LAGHTGYLSC C RFLDDNQI VTSSGDTTCA LWDIETGQQT TTFTGHTGDV MSLSLAPDTR LFVSGACDAS AKLWDVREGM CRQTFTGHES DI NAICFFP NGNAFATGSD DATCRLFDLR ADQELMTYSH DNIICGITSV SFSKSGRLLL AGYDDFNCNV WDALKADRAG VLA GHDNRV SCLGVTDDGM AVATGSWDSF LKIWN

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(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: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.845078 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFSAI L

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

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Macromolecule #4: Nb35

MacromoleculeName: Nb35 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 17.540746 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
MGMKYLLPTA AAGLLLLAAQ PAMAQVQLQE SGGGLVQPGG SLRLSCAASG FTFSNYKMNW VRQAPGKGLE WVSDISQSGA SISYTGSVK GRFTISRDNA KNTLYLQMNS LKPEDTAVYY CARCPAPFTR DCFDVTSTTY AYRGQGTQVT VSSHHHHHHE P EA

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Macromolecule #5: Soluble cytochrome b562,Trace amine-associated receptor 1

MacromoleculeName: Soluble cytochrome b562,Trace amine-associated receptor 1
type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 57.969645 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MKTIIALSYI FCLVFAGAPA DLEDNWETLN DNLKVIEKAD NAAQVKDALT KMRAAALDAQ KATPPKLEDK SPDSPEMKDF RHGFDILVG QIDDALKLAN EGKVKEAQAA AEQLKTTRNA YIQKYLMMPF CHNIINISCV KNNWSNDVRA SLYSLMVLII L TTLVGNLI ...String:
MKTIIALSYI FCLVFAGAPA DLEDNWETLN DNLKVIEKAD NAAQVKDALT KMRAAALDAQ KATPPKLEDK SPDSPEMKDF RHGFDILVG QIDDALKLAN EGKVKEAQAA AEQLKTTRNA YIQKYLMMPF CHNIINISCV KNNWSNDVRA SLYSLMVLII L TTLVGNLI VIVSISHFKQ LHTPTNWLIV SMATVDFLLG CLVMPYSMVR SAEHCWYFGE VFCKIHTSTD IMLSSASIWH LS FISIDRY YAVCDPLRYK AKMNILVICV MIFISWSVPA VFAFGMIFLE LNFKGAEEIY YKHVHCRGGC SVFFSKISGV LTF MTSFYI PGSIMLCVYY RIYLIAKEQA RLISDANQKL QIGLEMKNGI SQSKERKAVK TLGIVMGVFL ICWCPFFICT VMDP FLHYI IPPTLNDVLI WFGYLNSTFN PMVYAFFYPW FRKALKMMLF GKIFQKDSSR CKLFLELSSE FLEVLFQGPW SHPQF EKGG GSGGGSGGSA WSHPQFEKDY KDDDDK

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

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Macromolecule #6: (2S)-N-methyl-1-phenylpropan-2-amine

MacromoleculeName: (2S)-N-methyl-1-phenylpropan-2-amine / type: ligand / ID: 6 / Number of copies: 1 / Formula: B40
Molecular weightTheoretical: 149.233 Da
Chemical component information

ChemComp-B40:
(2S)-N-methyl-1-phenylpropan-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

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 54.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 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: 2.66 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 647397
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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