+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-16555 | |||||||||
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Title | Mouse serotonin 5-HT3A receptor in complex with PZ-1922 | |||||||||
Map data | ||||||||||
Sample |
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Keywords | Ion 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 / serotonin binding / excitatory extracellular ligand-gated monoatomic ion channel activity / inorganic cation transmembrane transport / cleavage furrow / transmembrane transporter complex / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential ...Neurotransmitter receptors and postsynaptic signal transmission / serotonin-gated monoatomic cation channel activity / serotonin-activated cation-selective channel complex / serotonin receptor signaling pathway / serotonin binding / excitatory extracellular ligand-gated monoatomic ion channel activity / inorganic cation transmembrane transport / 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 | |||||||||
Biological species | Mus musculus (house mouse) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.2 Å | |||||||||
Authors | Lopez-Sanchez U / Nury H | |||||||||
Funding support | European Union, 1 items
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Citation | Journal: 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 |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_16555.map.gz | 59.7 MB | EMDB map data format | |
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Header (meta data) | emd-16555-v30.xml emd-16555.xml | 15.7 KB 15.7 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_16555_fsc.xml | 8.4 KB | Display | FSC data file |
Images | emd_16555.png | 57.2 KB | ||
Masks | emd_16555_msk_1.map | 64 MB | Mask map | |
Filedesc metadata | emd-16555.cif.gz | 6 KB | ||
Others | emd_16555_half_map_1.map.gz emd_16555_half_map_2.map.gz | 59.3 MB 59.3 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-16555 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-16555 | HTTPS FTP |
-Validation report
Summary document | emd_16555_validation.pdf.gz | 842.8 KB | Display | EMDB validaton report |
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Full document | emd_16555_full_validation.pdf.gz | 842.4 KB | Display | |
Data in XML | emd_16555_validation.xml.gz | 16.5 KB | Display | |
Data in CIF | emd_16555_validation.cif.gz | 21.2 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-16555 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-16555 | HTTPS FTP |
-Related structure data
Related structure data | 8cc6MC 8cc7C M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_16555.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.145 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
File | emd_16555_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_16555_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_16555_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Mouse serotonin 5-HT3A receptor in complex with PZ-1922
Entire | Name: Mouse serotonin 5-HT3A receptor in complex with PZ-1922 |
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Components |
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-Supramolecule #1: Mouse serotonin 5-HT3A receptor in complex with PZ-1922
Supramolecule | Name: Mouse serotonin 5-HT3A receptor in complex with PZ-1922 type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: Mus musculus (house mouse) |
-Macromolecule #1: 5-hydroxytryptamine receptor 3A
Macromolecule | Name: 5-hydroxytryptamine receptor 3A / type: protein_or_peptide / ID: 1 / Number of copies: 5 / Enantiomer: LEVO |
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Source (natural) | Organism: Mus musculus (house mouse) |
Molecular weight | Theoretical: 63.682719 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: 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 |
-Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 5 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-Macromolecule #4: 1-[(3-chlorophenyl)methyl]-4-piperazin-1-yl-pyrrolo[3,2-c]quinoline
Macromolecule | Name: 1-[(3-chlorophenyl)methyl]-4-piperazin-1-yl-pyrrolo[3,2-c]quinoline type: ligand / ID: 4 / Number of copies: 5 / Formula: U9L |
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Molecular weight | Theoretical: 376.882 Da |
Chemical component information | ChemComp-U9L: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | TFS GLACIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 40.0 e/Å2 |
Electron beam | Acceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.3000000000000003 µm / Nominal defocus min: 0.7000000000000001 µm |