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- EMDB-36710: Structure of nanobody-bound DRD1_LSD complex -

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Entry
Database: EMDB / ID: EMD-36710
TitleStructure of nanobody-bound DRD1_LSD complex
Map data
Sample
  • Complex: nanobody-bound DRD1_LSD complex
    • Complex: DRD1
      • Protein or peptide: D(1A) dopamine receptor
      • Protein or peptide: NBA3
    • Complex: PrAC-PrAD-PrG
      • Protein or peptide: Maltose/maltodextrin-binding periplasmic protein,Immunoglobulin G-binding protein A,Immunoglobulin G-binding protein G
    • Complex: Fab 8D3
      • Protein or peptide: Fab 8D3 heavy chain
      • Protein or peptide: Fab 8D3 light chain
  • Ligand: (8alpha)-N,N-diethyl-6-methyl-9,10-didehydroergoline-8-carboxamide
KeywordsGPCR / DRD1 / LSD / MEMBRANE PROTEIN
Function / homology
Function and homology information


dopamine neurotransmitter receptor activity, coupled via Gs / dopamine neurotransmitter receptor activity / cerebral cortex GABAergic interneuron migration / operant conditioning / Dopamine receptors / dopamine binding / regulation of dopamine uptake involved in synaptic transmission / phospholipase C-activating dopamine receptor signaling pathway / peristalsis / heterotrimeric G-protein binding ...dopamine neurotransmitter receptor activity, coupled via Gs / dopamine neurotransmitter receptor activity / cerebral cortex GABAergic interneuron migration / operant conditioning / Dopamine receptors / dopamine binding / regulation of dopamine uptake involved in synaptic transmission / phospholipase C-activating dopamine receptor signaling pathway / peristalsis / heterotrimeric G-protein binding / modification of postsynaptic structure / G protein-coupled receptor complex / regulation of dopamine metabolic process / grooming behavior / positive regulation of neuron migration / habituation / sensitization / dopamine transport / astrocyte development / dentate gyrus development / conditioned taste aversion / striatum development / positive regulation of potassium ion transport / maternal behavior / arrestin family protein binding / non-motile cilium / long-term synaptic depression / IgG binding / mating behavior / adult walking behavior / G protein-coupled dopamine receptor signaling pathway / ciliary membrane / temperature homeostasis / detection of maltose stimulus / D-glucose import / maltose transport complex / dopamine metabolic process / transmission of nerve impulse / carbohydrate transport / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / carbohydrate transmembrane transporter activity / G-protein alpha-subunit binding / maltose binding / maltose transport / maltodextrin transmembrane transport / behavioral fear response / prepulse inhibition / neuronal action potential / activation of adenylate cyclase activity / behavioral response to cocaine / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / synapse assembly / adenylate cyclase-activating adrenergic receptor signaling pathway / presynaptic modulation of chemical synaptic transmission / response to amphetamine / positive regulation of synaptic transmission, glutamatergic / ATP-binding cassette (ABC) transporter complex / positive regulation of release of sequestered calcium ion into cytosol / cell chemotaxis / synaptic transmission, glutamatergic / G protein-coupled receptor activity / visual learning / GABA-ergic synapse / long-term synaptic potentiation / memory / adenylate cyclase-activating G protein-coupled receptor signaling pathway / protein import into nucleus / vasodilation / cellular response to catecholamine stimulus / adenylate cyclase-activating dopamine receptor signaling pathway / outer membrane-bounded periplasmic space / presynaptic membrane / G alpha (s) signalling events / dendritic spine / postsynaptic membrane / periplasmic space / positive regulation of MAPK cascade / cilium / positive regulation of cell migration / response to xenobiotic stimulus / DNA damage response / endoplasmic reticulum membrane / glutamatergic synapse / extracellular region / nucleus / membrane / plasma membrane
Similarity search - Function
Dopamine D1 receptor / Dopamine receptor family / Octapeptide repeat / Octapeptide repeat / Protein A, Ig-binding domain / B domain / IgG-binding B / B domain / M protein-type anchor domain / GA-like domain ...Dopamine D1 receptor / Dopamine receptor family / Octapeptide repeat / Octapeptide repeat / Protein A, Ig-binding domain / B domain / IgG-binding B / B domain / M protein-type anchor domain / GA-like domain / GA-like domain / Lysin motif / LysM domain superfamily / LysM domain / LysM domain profile. / LysM domain / Immunoglobulin/albumin-binding domain superfamily / YSIRK type signal peptide / YSIRK Gram-positive signal peptide / LPXTG cell wall anchor motif / Gram-positive cocci surface proteins LPxTG motif profile. / LPXTG cell wall anchor domain / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein / 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
Immunoglobulin G-binding protein G / Immunoglobulin G-binding protein A / Maltose/maltodextrin-binding periplasmic protein / D(1A) dopamine receptor / Immunoglobulin G-binding protein A
Similarity search - Component
Biological speciesHomo sapiens (human) / Escherichia coli O157:H7 (bacteria) / Mus musculus (house mouse) / Streptococcus sp. 'group G' (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.57 Å
AuthorsZhuang Y / Xu Y / Fan L / Wang S / Xu HE
Funding support China, 2 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32130022 China
National Natural Science Foundation of China (NSFC)82121005 China
CitationJournal: Neuron / Year: 2024
Title: Structural basis of psychedelic LSD recognition at dopamine D receptor.
Authors: Luyu Fan / Youwen Zhuang / Hongyu Wu / Huiqiong Li / Youwei Xu / Yue Wang / Licong He / Shishan Wang / Zhangcheng Chen / Jianjun Cheng / H Eric Xu / Sheng Wang /
Abstract: Understanding the kinetics of LSD in receptors and subsequent induced signaling is crucial for comprehending both the psychoactive and therapeutic effects of LSD. Despite extensive research on LSD's ...Understanding the kinetics of LSD in receptors and subsequent induced signaling is crucial for comprehending both the psychoactive and therapeutic effects of LSD. Despite extensive research on LSD's interactions with serotonin 2A and 2B receptors, its behavior on other targets, including dopamine receptors, has remained elusive. Here, we present cryo-EM structures of LSD/PF6142-bound dopamine D receptor (DRD1)-legobody complexes, accompanied by a β-arrestin-mimicking nanobody, NBA3, shedding light on the determinants of G protein coupling versus β-arrestin coupling. Structural analysis unveils a distinctive binding mode of LSD in DRD1, particularly with the ergoline moiety oriented toward TM4. Kinetic investigations uncover an exceptionally rapid dissociation rate of LSD in DRD1, attributed to the flexibility of extracellular loop 2 (ECL2). Moreover, G protein can stabilize ECL2 conformation, leading to a significant slowdown in ligand's dissociation rate. These findings establish a solid foundation for further exploration of G protein-coupled receptor (GPCR) dynamics and their relevance to signal transduction.
History
DepositionJul 1, 2023-
Header (metadata) releaseSep 4, 2024-
Map releaseSep 4, 2024-
UpdateOct 30, 2024-
Current statusOct 30, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_36710.png

Downloads & links

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Map

FileDownload / File: emd_36710.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 256 pix.
= 210.944 Å		0.82 Å/pix.
x 256 pix.
= 210.944 Å		0.82 Å/pix.
x 256 pix.
= 210.944 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.824 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.009
Minimum - Maximum-0.042842638 - 0.060792845
Average (Standard dev.)-0.0000074184377 (±0.0017191325)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 210.944 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : nanobody-bound DRD1_LSD complex

EntireName: nanobody-bound DRD1_LSD complex
Components
  • Complex: nanobody-bound DRD1_LSD complex
    • Complex: DRD1
      • Protein or peptide: D(1A) dopamine receptor
      • Protein or peptide: NBA3
    • Complex: PrAC-PrAD-PrG
      • Protein or peptide: Maltose/maltodextrin-binding periplasmic protein,Immunoglobulin G-binding protein A,Immunoglobulin G-binding protein G
    • Complex: Fab 8D3
      • Protein or peptide: Fab 8D3 heavy chain
      • Protein or peptide: Fab 8D3 light chain
  • Ligand: (8alpha)-N,N-diethyl-6-methyl-9,10-didehydroergoline-8-carboxamide

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Supramolecule #1: nanobody-bound DRD1_LSD complex

SupramoleculeName: nanobody-bound DRD1_LSD complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Molecular weightTheoretical: 170 KDa

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Supramolecule #2: DRD1

SupramoleculeName: DRD1 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: PrAC-PrAD-PrG

SupramoleculeName: PrAC-PrAD-PrG / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3
Source (natural)Organism: Escherichia coli O157:H7 (bacteria)

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Supramolecule #4: Fab 8D3

SupramoleculeName: Fab 8D3 / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #4-#5
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: D(1A) dopamine receptor

MacromoleculeName: D(1A) dopamine receptor / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.187793 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GTGLVVERDF SVRILTACFL SLLILSTLLG NTLVCAAVIR FRHLRSKVTN FFVISLAVSD LLVAVLVMPW KAVAEIAGFW PFGSFCNIW VAFDIMCSTA SIWNLCVISV DRYWAISSPF RYERKMTPKA AFILISVAWT LSVLISFIPV QLSWHKAKPT S PSDGNATS ...String:
GTGLVVERDF SVRILTACFL SLLILSTLLG NTLVCAAVIR FRHLRSKVTN FFVISLAVSD LLVAVLVMPW KAVAEIAGFW PFGSFCNIW VAFDIMCSTA SIWNLCVISV DRYWAISSPF RYERKMTPKA AFILISVAWT LSVLISFIPV QLSWHKAKPT S PSDGNATS LAETIDNCDS SLSRTYAISS SVISFYIPVA IMIVTYTRIY RIAQKQIRRI AALERAAVHA KNCQTTTGNG KP VECSQPE SSFKMSFKRE TKVLKTLSVI MGVFVCCWLP FFILNCILPF CGSGETQPFC IDSNTFDVFV WFGWANSALN PII YAFNAD FRKAFSTLLG CYRLCPATNN AIETVS

UniProtKB: D(1A) dopamine receptor

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Macromolecule #2: NBA3

MacromoleculeName: NBA3 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.493983 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
QVQLQESGGG LVQAGGSLRL SCAASGSIFA LNIMGWYRQA PGKQRELVAA IHSGGTTNYA NSVKGRFTIS RDNAANTVYL QMNSLKPED TAVYYCNVKD FGAIVADRDY WGQGTQVTVS SLEHHH

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Macromolecule #3: Maltose/maltodextrin-binding periplasmic protein,Immunoglobulin G...

MacromoleculeName: Maltose/maltodextrin-binding periplasmic protein,Immunoglobulin G-binding protein A,Immunoglobulin G-binding protein G
type: protein_or_peptide / ID: 3 / Details: reference: 7RXC / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Streptococcus sp. 'group G' (bacteria)
Molecular weightTheoretical: 60.575715 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGSSHHHHHH SSGLVPRGSH MKIEEGKLVI WINGDKGYNG LAEVGKKFEK DTGIKVTVEH PDKLEEKFPQ VAATGDGPDI IFWAHDRFG GYAQSGLLAE ITPDKAFQDK LYPFTWDAVR YNGKLIAYPI AVEALSLIYN KDLLPNPPKT WEEIPALDKE L KAKGKSAL ...String:
MGSSHHHHHH SSGLVPRGSH MKIEEGKLVI WINGDKGYNG LAEVGKKFEK DTGIKVTVEH PDKLEEKFPQ VAATGDGPDI IFWAHDRFG GYAQSGLLAE ITPDKAFQDK LYPFTWDAVR YNGKLIAYPI AVEALSLIYN KDLLPNPPKT WEEIPALDKE L KAKGKSAL MFNLQEPYFT WPLIAADGGY AFKYENGKYD IKDVGVDNAG AKAGLTFLVD LIKNKHMNAD TDYSIAEAAF NK GETAMTI NGPWAWSNID TSKVNYGVTV LPTFKGQPSK PFVGVLSAGI NAASPNKELA KEFLENYLLT DEGLEAVNKD KPL GAVALK SYEEELAKDP RIAATMENAQ KGEIMPNIPQ MSAFWYAVRT AVINAASGRQ TVDQALAFAQ ILIMPNLTEE QRNG FIQSL KDDPSVSKEI LAEAKKLNEH QAPKGGSGGA GSGDQQSAFY EILNMPNLNE AQRNGFIQSL KDDPSQSTNV LGEAK KLNE SQAGGGSGGG SGGSAVTTYK LVINGKTLKG ETTTKAVDAE TAEKAFKQYA NDNGVDGVWT YDDATKTFTV TEGSG

UniProtKB: Maltose/maltodextrin-binding periplasmic protein, Immunoglobulin G-binding protein A, Immunoglobulin G-binding protein A, Immunoglobulin G-binding protein G

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Macromolecule #4: Fab 8D3 heavy chain

MacromoleculeName: Fab 8D3 heavy chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 27.396742 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MDWTWRVFCL LAVAPGAHSD VQLVESGGGL VQPGKSLRLS CAASGFTFSN FGMHWVRQAP EMGLEWVAYI SSGSTTKYYG DTVKGRFTI SRDNPKNTLY LQMNSLRSED TAMYYCARRP LYDGDYGYPM DYWGQGTSVT VSSASTKGPS VFPLAPSSKS T SGGTAALG ...String:
MDWTWRVFCL LAVAPGAHSD VQLVESGGGL VQPGKSLRLS CAASGFTFSN FGMHWVRQAP EMGLEWVAYI SSGSTTKYYG DTVKGRFTI SRDNPKNTLY LQMNSLRSED TAMYYCARRP LYDGDYGYPM DYWGQGTSVT VSSASTKGPS VFPLAPSSKS T SGGTAALG CLVKDYFPEP VTVSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL GTQTYICNVN HKPSNTKVDK KV EPKSCGS HHHHHH

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Macromolecule #5: Fab 8D3 light chain

MacromoleculeName: Fab 8D3 light chain / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 26.317523 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MVLQTQVFIS LLLWISGAYG NIMLTQSPSS LAVSAGERVT MSCKSTQSIL YNSNQKTYLA WYQQKPGQSP KLLIYWASTR ASGVPDRFT GSGSGTDFTL TINSVQPEDL AVYYCHQYLS AWTFGGGTKL EIKRTVAAPS VFIFPPSDEQ LKSGTASVVC L LNNFYPRE ...String:
MVLQTQVFIS LLLWISGAYG NIMLTQSPSS LAVSAGERVT MSCKSTQSIL YNSNQKTYLA WYQQKPGQSP KLLIYWASTR ASGVPDRFT GSGSGTDFTL TINSVQPEDL AVYYCHQYLS AWTFGGGTKL EIKRTVAAPS VFIFPPSDEQ LKSGTASVVC L LNNFYPRE AKVQWKVDNA LQSGNSQESV TEQDSKDSTY SLSSTLTLSK ADYEKHKVYA CEVTHQGLSS PVTKSFNRGE C

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Macromolecule #7: (8alpha)-N,N-diethyl-6-methyl-9,10-didehydroergoline-8-carboxamide

MacromoleculeName: (8alpha)-N,N-diethyl-6-methyl-9,10-didehydroergoline-8-carboxamide
type: ligand / ID: 7 / Number of copies: 1 / Formula: 7LD
Molecular weightTheoretical: 323.432 Da
Chemical component information

ChemComp-7LD:
(8alpha)-N,N-diethyl-6-methyl-9,10-didehydroergoline-8-carboxamide

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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: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 5.0 µm / Nominal defocus min: 1.2 µm
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:

7ljd

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.57 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 175144
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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