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- EMDB-10673: Mouse serotonin 5HT3 receptor in complex with palonosetron -

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Basic information

Entry
Database: EMDB / ID: EMD-10673
TitleMouse serotonin 5HT3 receptor in complex with palonosetron
Map dataMouse serotonin 5HT3 receptor bound to palonosetron
Sample
  • Complex: Mouse serotonin 5-HT3 receptor in complex with palonosetron
    • Protein or peptide: 5-hydroxytryptamine receptor 3A
  • Ligand: TRYPTOPHAN
  • Ligand: HISTIDINE
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (3~{a}~{S})-2-[(3~{S})-1-azabicyclo[2.2.2]octan-3-yl]-3~{a},4,5,6-tetrahydro-3~{H}-benzo[de]isoquinolin-1-one
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 / acetylcholine-gated monoatomic cation-selective channel activity / inorganic cation transmembrane transport / cleavage furrow / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / presynaptic membrane ...Neurotransmitter receptors and postsynaptic signal transmission / serotonin-gated monoatomic cation channel activity / serotonin-activated cation-selective channel complex / serotonin receptor signaling pathway / serotonin binding / acetylcholine-gated monoatomic cation-selective channel activity / inorganic cation transmembrane transport / cleavage furrow / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / presynaptic membrane / postsynaptic membrane / neuron projection / axon / neuronal cell body / glutamatergic synapse / synapse / identical protein binding
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: 2.82 Å
AuthorsZarkadas E / Perot J / Nury H
Funding support France, 1 items
OrganizationGrant numberCountry
European Research Council (ERC)637733 France
CitationJournal: Structure / Year: 2020
Title: The Binding of Palonosetron and Other Antiemetic Drugs to the Serotonin 5-HT3 Receptor.
Authors: Eleftherios Zarkadas / Hong Zhang / Wensheng Cai / Gregory Effantin / Jonathan Perot / Jacques Neyton / Christophe Chipot / Guy Schoehn / Francois Dehez / Hugues Nury /
Abstract: Inaccurately perceived as niche drugs, antiemetics are key elements of cancer treatment alleviating the most dreaded side effect of chemotherapy. Serotonin 5-HT3 receptor antagonists are the most ...Inaccurately perceived as niche drugs, antiemetics are key elements of cancer treatment alleviating the most dreaded side effect of chemotherapy. Serotonin 5-HT3 receptor antagonists are the most commonly prescribed class of drugs to control chemotherapy-induced nausea and vomiting. These antagonists have been clinically successful drugs since the 1980s, yet our understanding of how they operate at the molecular level has been hampered by the difficulty of obtaining structures of drug-receptor complexes. Here, we report the cryoelectron microscopy structure of the palonosetron-bound 5-HT3 receptor. We investigate the binding of palonosetron, granisetron, dolasetron, ondansetron, and cilansetron using molecular dynamics, covering the whole set of antagonists used in clinical practice. The structural and computational results yield detailed atomic insight into the binding modes of the drugs. In light of our data, we establish a comprehensive framework underlying the inhibition mechanism by the -setron drug family.
History
DepositionFeb 14, 2020-
Header (metadata) releaseMar 4, 2020-
Map releaseMar 4, 2020-
UpdateSep 14, 2022-
Current statusSep 14, 2022Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.697
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 0.697
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6y1z
  • Surface level: 0.55
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_10673.png

Downloads & links

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Map

FileDownload / File: emd_10673.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMouse serotonin 5HT3 receptor bound to palonosetron
Voxel sizeX=Y=Z: 1.067 Å
Density
Contour LevelBy AUTHOR: 0.697 / Movie #1: 0.697
Minimum - Maximum-2.4400642 - 4.1492605
Average (Standard dev.)0.011694383 (±0.1131419)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 256.08002 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0671.0671.067
M x/y/z240240240
origin x/y/z0.0000.0000.000
length x/y/z256.080256.080256.080
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ256256256
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS240240240
D min/max/mean-2.4404.1490.012

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Supplemental data

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Sample components

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Entire : Mouse serotonin 5-HT3 receptor in complex with palonosetron

EntireName: Mouse serotonin 5-HT3 receptor in complex with palonosetron
Components
  • Complex: Mouse serotonin 5-HT3 receptor in complex with palonosetron
    • Protein or peptide: 5-hydroxytryptamine receptor 3A
  • Ligand: TRYPTOPHAN
  • Ligand: HISTIDINE
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (3~{a}~{S})-2-[(3~{S})-1-azabicyclo[2.2.2]octan-3-yl]-3~{a},4,5,6-tetrahydro-3~{H}-benzo[de]isoquinolin-1-one

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Supramolecule #1: Mouse serotonin 5-HT3 receptor in complex with palonosetron

SupramoleculeName: Mouse serotonin 5-HT3 receptor in complex with palonosetron
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mus musculus (house mouse)
Recombinant expressionOrganism: Homo sapiens (human)

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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

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Macromolecule #4: TRYPTOPHAN

MacromoleculeName: TRYPTOPHAN / type: ligand / ID: 4 / Number of copies: 5 / Formula: TRP
Molecular weightTheoretical: 204.225 Da
Chemical component information

ChemComp-TRP:
TRYPTOPHAN / Tryptophan

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Macromolecule #5: HISTIDINE

MacromoleculeName: HISTIDINE / type: ligand / ID: 5 / Number of copies: 5 / Formula: HIS
Molecular weightTheoretical: 156.162 Da
Chemical component information

ChemComp-HIS:
HISTIDINE / Histidine

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 5 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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Macromolecule #7: (3~{a}~{S})-2-[(3~{S})-1-azabicyclo[2.2.2]octan-3-yl]-3~{a},4,5,6...

MacromoleculeName: (3~{a}~{S})-2-[(3~{S})-1-azabicyclo[2.2.2]octan-3-yl]-3~{a},4,5,6-tetrahydro-3~{H}-benzo[de]isoquinolin-1-one
type: ligand / ID: 7 / Number of copies: 5 / Formula: O7B
Molecular weightTheoretical: 296.407 Da
Chemical component information

ChemComp-O7B:
(3~{a}~{S})-2-[(3~{S})-1-azabicyclo[2.2.2]octan-3-yl]-3~{a},4,5,6-tetrahydro-3~{H}-benzo[de]isoquinolin-1-one / medication, chemotherapy, antagonist*YM / Palonosetron

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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 / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 53.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

0227

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C5 (5 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.82 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. v2.13) / Number images used: 127971

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