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- PDB-8jxr: Structure of nanobody-bound DRD1_LSD complex -

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Basic information

Entry
Database: PDB / ID: 8jxr
TitleStructure of nanobody-bound DRD1_LSD 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 / LSD
Function / homology
Function and homology information


dopamine neurotransmitter receptor activity, coupled via Gs / dopamine neurotransmitter receptor activity / operant conditioning / cerebral cortex GABAergic interneuron migration / 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 / operant conditioning / cerebral cortex GABAergic interneuron migration / 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 / positive regulation of neuron migration / grooming behavior / habituation / sensitization / dopamine transport / astrocyte development / dentate gyrus development / striatum development / conditioned taste aversion / 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 / carbohydrate transmembrane transporter activity / G-protein alpha-subunit binding / maltose binding / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / maltose transport / maltodextrin transmembrane transport / prepulse inhibition / positive regulation of synaptic transmission, glutamatergic / behavioral fear response / neuronal action potential / ATP-binding cassette (ABC) transporter complex, substrate-binding subunit-containing / synapse assembly / behavioral response to cocaine / adenylate cyclase-activating adrenergic receptor signaling pathway / presynaptic modulation of chemical synaptic transmission / ATP-binding cassette (ABC) transporter complex / response to amphetamine / positive regulation of release of sequestered calcium ion into cytosol / cell chemotaxis / synaptic transmission, glutamatergic / G protein-coupled receptor activity / GABA-ergic synapse / visual learning / vasodilation / memory / adenylate cyclase-activating G protein-coupled receptor signaling pathway / long-term synaptic potentiation / protein import into nucleus / 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
alpha-maltose / Chem-7LD / 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)
Staphylococcus aureus (bacteria)
Staphylococcus aureus subsp. aureus Mu50 (bacteria)
Streptococcus sp. 'group G' (bacteria)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.57 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 30, 2024Group: Data collection / Database references / Structure summary
Category: citation / em_admin ...citation / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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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)167,6377
Polymers166,9725
Non-polymers6662
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 / MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP / IgG-binding protein A / ...MMBP / Maltodextrin-binding protein / Maltose-binding protein / MBP / 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
Source method: isolated from a genetically manipulated source
Details: reference: 7RXC
Source: (gene. exp.) Escherichia coli O157:H7 (bacteria), (gene. exp.) Staphylococcus aureus (bacteria), (gene. exp.) Staphylococcus aureus subsp. aureus Mu50 (bacteria), (gene. exp.) Streptococcus ...Source: (gene. exp.) Escherichia coli O157:H7 (bacteria), (gene. exp.) Staphylococcus aureus (bacteria), (gene. exp.) Staphylococcus aureus subsp. aureus Mu50 (bacteria), (gene. exp.) Streptococcus sp. 'group G' (bacteria)
Gene: malE, b4034, JW3994, 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 / Sugars / Non-polymers , 3 types, 3 molecules A

#1: Protein D(1A) dopamine receptor / Dopamine D1 receptor / DRD1


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: Polysaccharide alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose


Type: oligosaccharide, Oligosaccharide / Class: Nutrient / Mass: 342.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: oligosaccharide / References: alpha-maltose
DescriptorTypeProgram
DGlcpa1-4DGlcpa1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1a_1-5]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][a-D-Glcp]{[(4+1)][a-D-Glcp]{}}LINUCSPDB-CARE
#7: Chemical ChemComp-7LD / (8alpha)-N,N-diethyl-6-methyl-9,10-didehydroergoline-8-carboxamide / Lysergic acid diethylamide


Mass: 323.432 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H25N3O / Feature type: SUBJECT OF INVESTIGATION

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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_LSD complexCOMPLEX#1-#50RECOMBINANT
2DRD1COMPLEX#1-#21RECOMBINANT
3PrAC-PrAD-PrGCOMPLEX#31RECOMBINANT
4Fab 8D3COMPLEX#4-#51RECOMBINANT
Molecular weightValue: 0.17 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Escherichia coli O157:H7 (bacteria)83334
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: 3.57 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 175144 / Symmetry type: POINT

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