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- EMDB-16557: Mouse serotonin 5-HT3A receptor in complex with PZ-1939 -

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Basic information

Entry
Database: EMDB / ID: EMD-16557
TitleMouse serotonin 5-HT3A receptor in complex with PZ-1939
Map data
Sample
  • Complex: Mouse serotonin 5-HT3A receptor in complex with PZ-1922
    • Protein or peptide: 5-hydroxytryptamine receptor 3A
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 1-(3-chlorophenyl)sulfonyl-4-piperazin-1-yl-pyrrolo[3,2-c]quinoline
KeywordsIon channel / Receptor / pLGIC / TRANSPORT PROTEIN
Function / homology
Function and homology information


Neurotransmitter receptors and postsynaptic signal transmission / serotonin-gated monoatomic cation channel activity / serotonin-activated cation-selective channel complex / serotonin receptor signaling pathway / excitatory extracellular ligand-gated monoatomic ion channel activity / serotonin binding / inorganic cation transmembrane transport / acetylcholine-gated monoatomic cation-selective channel activity / cleavage furrow / transmembrane transporter complex ...Neurotransmitter receptors and postsynaptic signal transmission / serotonin-gated monoatomic cation channel activity / serotonin-activated cation-selective channel complex / serotonin receptor signaling pathway / excitatory extracellular ligand-gated monoatomic ion channel activity / serotonin binding / inorganic cation transmembrane transport / acetylcholine-gated monoatomic cation-selective channel activity / cleavage furrow / transmembrane transporter complex / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / presynaptic membrane / postsynaptic membrane / neuron projection / axon / neuronal cell body / glutamatergic synapse / synapse / identical protein binding / plasma membrane
Similarity search - Function
5-hydroxytryptamine 3 receptor / 5-hydroxytryptamine 3 receptor, A subunit / Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channels signature. / Neurotransmitter-gated ion-channel transmembrane domain / Neurotransmitter-gated ion-channel transmembrane region / Neurotransmitter-gated ion-channel transmembrane domain superfamily / Neuronal acetylcholine receptor / Neurotransmitter-gated ion-channel / Neurotransmitter-gated ion-channel ligand-binding domain ...5-hydroxytryptamine 3 receptor / 5-hydroxytryptamine 3 receptor, A subunit / Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channels signature. / Neurotransmitter-gated ion-channel transmembrane domain / Neurotransmitter-gated ion-channel transmembrane region / Neurotransmitter-gated ion-channel transmembrane domain superfamily / Neuronal acetylcholine receptor / Neurotransmitter-gated ion-channel / Neurotransmitter-gated ion-channel ligand-binding domain / Neurotransmitter-gated ion-channel ligand-binding domain superfamily / Neurotransmitter-gated ion-channel ligand binding domain
Similarity search - Domain/homology
5-hydroxytryptamine receptor 3A
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsLopez-Sanchez U / Nury H
Funding supportEuropean Union, 1 items
OrganizationGrant numberCountry
European Research Council (ERC)PentaBrainEuropean Union
CitationJournal: J Med Chem / Year: 2023
Title: Superiority of the Triple-Acting 5-HTR/5-HTR Antagonist and MAO-B Reversible Inhibitor over 5-HTR Antagonist Intepirdine in Alleviation of Cognitive Deficits in Rats.
Authors: Katarzyna Grychowska / Uriel López-Sánchez / Mathieu Vitalis / Geoffrey Canet / Grzegorz Satała / Agnieszka Olejarz-Maciej / Joanna Gołębiowska / Rafał Kurczab / Wojciech Pietruś / ...Authors: Katarzyna Grychowska / Uriel López-Sánchez / Mathieu Vitalis / Geoffrey Canet / Grzegorz Satała / Agnieszka Olejarz-Maciej / Joanna Gołębiowska / Rafał Kurczab / Wojciech Pietruś / Monika Kubacka / Christophe Moreau / Maria Walczak / Klaudia Blicharz-Futera / Ophélie Bento / Xavier Bantreil / Gilles Subra / Andrzej J Bojarski / Frédéric Lamaty / Carine Becamel / Charleine Zussy / Séverine Chaumont-Dubel / Piotr Popik / Hugues Nury / Philippe Marin / Laurent Givalois / Paweł Zajdel /
Abstract: The multifactorial origin and neurochemistry of Alzheimer's disease (AD) call for the development of multitarget treatment strategies. We report a first-in-class triple acting compound that targets ...The multifactorial origin and neurochemistry of Alzheimer's disease (AD) call for the development of multitarget treatment strategies. We report a first-in-class triple acting compound that targets serotonin type 6 and 3 receptors (5-HT-Rs) and monoamine oxidase type B (MAO-B) as an approach for treating AD. The key structural features required for MAO-B inhibition and 5-HTR antagonism and interaction with 5-HTR were determined using molecular dynamic simulations and cryo-electron microscopy, respectively. Bioavailable reversed scopolamine-induced cognitive deficits in the novel object recognition test. Furthermore, it displayed superior pro-cognitive properties compared to intepirdine (a 5-HTR antagonist) in the AD model, which involved intracerebroventricular injection of an oligomeric solution of amyloid-β peptide (oAβ) in the T-maze test in rats. , but not intepirdine, restored levels of biomarkers characteristic of the debilitating effects of oAβ. These data support the potential of a multitarget approach involving the joint modulation of 5-HTR/5-HTR/MAO-B in AD.
History
DepositionJan 26, 2023-
Header (metadata) releaseOct 11, 2023-
Map releaseOct 11, 2023-
UpdateNov 22, 2023-
Current statusNov 22, 2023Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_16557.png

Downloads & links

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Map

FileDownload / File: emd_16557.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.15 Å/pix.
x 256 pix.
= 293.12 Å		1.15 Å/pix.
x 256 pix.
= 293.12 Å		1.15 Å/pix.
x 256 pix.
= 293.12 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.145 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.253
Minimum - Maximum-1.199935 - 2.010612
Average (Standard dev.)-0.0010772168 (±0.051673945)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 293.12 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_16557_msk_1.map
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Half map: #1

Fileemd_16557_half_map_1.map
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Half map: #2

Fileemd_16557_half_map_2.map
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Sample components

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Entire : Mouse serotonin 5-HT3A receptor in complex with PZ-1922

EntireName: Mouse serotonin 5-HT3A receptor in complex with PZ-1922
Components
  • Complex: Mouse serotonin 5-HT3A receptor in complex with PZ-1922
    • Protein or peptide: 5-hydroxytryptamine receptor 3A
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 1-(3-chlorophenyl)sulfonyl-4-piperazin-1-yl-pyrrolo[3,2-c]quinoline

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Supramolecule #1: Mouse serotonin 5-HT3A receptor in complex with PZ-1922

SupramoleculeName: Mouse serotonin 5-HT3A receptor in complex with PZ-1922
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: 5-hydroxytryptamine receptor 3A

MacromoleculeName: 5-hydroxytryptamine receptor 3A / type: protein_or_peptide / ID: 1 / Number of copies: 5 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 63.682719 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MRLCIPQVLL ALFLSMLTGP GEGSRRRWSH PQFEKGGGSG GGSGGGSWSH PQFEKGGGSG GGSGGGSWSH PQFEKGGGSG GGSGGGSWS HPQFEKENLY FQGSGATQAR DTTQPALLRL SDHLLANYKK GVRPVRDWRK PTTVSIDVIM YAILNVDEKN Q VLTTYIWY ...String:
MRLCIPQVLL ALFLSMLTGP GEGSRRRWSH PQFEKGGGSG GGSGGGSWSH PQFEKGGGSG GGSGGGSWSH PQFEKGGGSG GGSGGGSWS HPQFEKENLY FQGSGATQAR DTTQPALLRL SDHLLANYKK GVRPVRDWRK PTTVSIDVIM YAILNVDEKN Q VLTTYIWY RQYWTDEFLQ WTPEDFDNVT KLSIPTDSIW VPDILINEFV DVGKSPNIPY VYVHHRGEVQ NYKPLQLVTA CS LDIYNFP FDVQNCSLTF TSWLHTIQDI NITLWRSPEE VRSDKSIFIN QGEWELLEVF PQFKEFSIDI SNSYAEMKFY VII RRRPLF YAVSLLLPSI FLMVVDIVGF CLPPDSGERV SFKITLLLGY SVFLIIVSDT LPATAIGTPL IGVYFVVCMA LLVI SLAET IFIVRLVHKQ DLQRPVPDWL RHLVLDRIAW ILCLGEQPMA HRPPATFQAN KTDDCSGSDL LPAMGNHCSH VGGPQ DLEK TPRGRGSPLP PPREASLAVR GLLQELSSIR HFLEKRDEMR EVARDWLRVG YVLDRLLFRI YLLAVLAYSI TLVTLW SIW HSS

UniProtKB: 5-hydroxytryptamine receptor 3A

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 5 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #4: 1-(3-chlorophenyl)sulfonyl-4-piperazin-1-yl-pyrrolo[3,2-c]quinoline

MacromoleculeName: 1-(3-chlorophenyl)sulfonyl-4-piperazin-1-yl-pyrrolo[3,2-c]quinoline
type: ligand / ID: 4 / Number of copies: 5 / Formula: U9Q
Molecular weightTheoretical: 426.919 Da
Chemical component information

ChemComp-U9Q:
1-(3-chlorophenyl)sulfonyl-4-piperazin-1-yl-pyrrolo[3,2-c]quinoline

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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

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.3000000000000003 µm / Nominal defocus min: 0.7000000000000001 µm

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6y1z

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 102137
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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