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- PDB-8jxs: Structure of nanobody-bound DRD1_PF-6142 complex -

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Basic information

Entry
Database: PDB / ID: 8jxs
TitleStructure of nanobody-bound DRD1_PF-6142 complex
Components
  • D(1A) dopamine receptor
  • Fab 8D3 heavy chain
  • Fab 8D3 light chain
  • Maltose/maltodextrin-binding periplasmic protein,Immunoglobulin G-binding protein A,Immunoglobulin G-binding protein G
  • NBA3
KeywordsMEMBRANE PROTEIN / GPCR / DRD1 / PF-6142
Function / homology
Function and homology information


dopamine neurotransmitter receptor activity, coupled via Gs / dopamine neurotransmitter receptor activity / cerebral cortex GABAergic interneuron migration / Dopamine receptors / regulation of dopamine uptake involved in synaptic transmission / dopamine binding / phospholipase C-activating dopamine receptor signaling pathway / heterotrimeric G-protein binding / 9+0 non-motile cilium / G protein-coupled receptor complex ...dopamine neurotransmitter receptor activity, coupled via Gs / dopamine neurotransmitter receptor activity / cerebral cortex GABAergic interneuron migration / Dopamine receptors / regulation of dopamine uptake involved in synaptic transmission / dopamine binding / phospholipase C-activating dopamine receptor signaling pathway / heterotrimeric G-protein binding / 9+0 non-motile cilium / G protein-coupled receptor complex / modification of postsynaptic structure / adult walking behavior / positive regulation of potassium ion transport / arrestin family protein binding / non-motile cilium / G protein-coupled dopamine receptor signaling pathway / IgG binding / mating behavior / ciliary membrane / dopamine metabolic process / detection of maltose stimulus / transmission of nerve impulse / carbohydrate transport / carbohydrate transmembrane transporter activity / maltose binding / G-protein alpha-subunit binding / maltose transport / maltodextrin transmembrane transport / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / adenylate cyclase-activating adrenergic receptor signaling pathway / positive regulation of synaptic transmission, glutamatergic / synapse assembly / presynaptic modulation of chemical synaptic transmission / visual learning / ATP-binding cassette (ABC) transporter complex / positive regulation of release of sequestered calcium ion into cytosol / cell chemotaxis / vasodilation / GABA-ergic synapse / G protein-coupled receptor activity / cilium / cellular response to catecholamine stimulus / adenylate cyclase-activating dopamine receptor signaling pathway / outer membrane-bounded periplasmic space / adenylate cyclase-activating G protein-coupled receptor signaling pathway / presynaptic membrane / dendritic spine / G alpha (s) signalling events / positive regulation of MAPK cascade / periplasmic space / postsynaptic membrane / response to xenobiotic stimulus / positive regulation of cell migration / DNA damage response / endoplasmic reticulum membrane / glutamatergic synapse / membrane / nucleus / 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. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile.
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 K-12 (bacteria)
Staphylococcus aureus (bacteria)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsZhuang, Y. / Xu, Y. / Fan, L. / Wang, S. / Xu, H.E.
Funding support China, 2items
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, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 4, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.2Oct 30, 2024Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.page_first / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: D(1A) dopamine receptor
B: NBA3
C: Maltose/maltodextrin-binding periplasmic protein,Immunoglobulin G-binding protein A,Immunoglobulin G-binding protein G
H: Fab 8D3 heavy chain
L: Fab 8D3 light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)167,3286
Polymers166,9725
Non-polymers3561
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Antibody , 4 types, 4 molecules BCHL

#2: Antibody NBA3


Mass: 13493.983 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)
#3: Antibody Maltose/maltodextrin-binding periplasmic protein,Immunoglobulin G-binding protein A,Immunoglobulin G-binding protein G / IgG-binding protein A / Staphylococcal protein A / SpA / IgG-binding protein G


Mass: 60575.715 Da / Num. of mol.: 1 / Mutation: E360Q,K363A,D364F,T367I,R368L,D404E,A405H
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli K-12 (bacteria), (gene. exp.) Staphylococcus aureus (bacteria)
Gene: malE, spa, spa, SAV0111, spg / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P0AEX9, UniProt: P38507, UniProt: P0A015, UniProt: P06654
#4: Antibody Fab 8D3 heavy chain


Mass: 27396.742 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)
#5: Antibody Fab 8D3 light chain


Mass: 26317.523 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)

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Protein / Non-polymers , 2 types, 2 molecules A

#1: Protein D(1A) dopamine receptor / Dopamine D1 receptor


Mass: 39187.793 Da / Num. of mol.: 1 / Mutation: L112W,S325A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DRD1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P21728
#6: Chemical ChemComp-V6X / 4-[3-methyl-4-(6-methylimidazo[1,2-a]pyrazin-5-yl)phenoxy]furo[3,2-c]pyridine / PF-6142


Mass: 356.377 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H16N4O2

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1nanobody-bound DRD1_PF-6142 complexCOMPLEX#1-#50RECOMBINANT
2DRD1COMPLEX#1-#21RECOMBINANT
3PrAC-PrAD-PrGCOMPLEX#31RECOMBINANT
4FabCOMPLEX#4-#51RECOMBINANT
Molecular weightValue: 0.17 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Escherichia coli (E. coli)83333
43Staphylococcus aureus (bacteria)1280
54Mus musculus (house mouse)10090
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 5000 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 104462 / Symmetry type: POINT

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