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- EMDB-21512: Cryo-EM structure of 5HT3A receptor in presence of Ondansetron -

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Basic information

Entry
Database: EMDB / ID: EMD-21512
TitleCryo-EM structure of 5HT3A receptor in presence of Ondansetron
Map data5HT3A receptor in presence of Ondansetron
Sample
  • Complex: Serotonin receptor5-HT receptor
    • Protein or peptide: 5-hydroxytryptamine receptor 3A
  • Ligand: ondansetron
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 / extracellular ligand-gated monoatomic ion channel activity / cleavage furrow / 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 / acetylcholine-gated monoatomic cation-selective channel activity / inorganic cation transmembrane transport / extracellular ligand-gated monoatomic ion channel activity / cleavage furrow / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / transmembrane signaling receptor activity / 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 / 5-hydroxytryptamine (serotonin) receptor 3A
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.06 Å
AuthorsBasak S / Chakrapani S
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)1R01GM108921 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)3R01GM108921-03S1 United States
CitationJournal: Nat Commun / Year: 2019
Title: Molecular mechanism of setron-mediated inhibition of full-length 5-HT receptor.
Authors: Sandip Basak / Yvonne Gicheru / Abhijeet Kapoor / Megan L Mayer / Marta Filizola / Sudha Chakrapani /
Abstract: Serotonin receptor (5-HTR) is the most common therapeutic target to manage the nausea and vomiting during cancer therapies and in the treatment of irritable bowel syndrome. Setrons, a class of ...Serotonin receptor (5-HTR) is the most common therapeutic target to manage the nausea and vomiting during cancer therapies and in the treatment of irritable bowel syndrome. Setrons, a class of competitive antagonists, cause functional inhibition of 5-HTR in the gastrointestinal tract and brainstem, acting as effective anti-emetic agents. Despite their prevalent use, the molecular mechanisms underlying setron binding and inhibition of 5-HTR are not fully understood. Here, we present the structure of granisetron-bound full-length 5-HTR solved by single-particle cryo-electron microscopy to 2.92 Å resolution. The reconstruction reveals the orientation of granisetron in the orthosteric site with unambiguous density for interacting sidechains. Molecular dynamics simulations and electrophysiology confirm the granisetron binding orientation and the residues central for ligand recognition. Comparison of granisetron-bound 5-HTR with the apo and serotonin-bound structures, reveals key insights into the mechanism underlying 5-HTR inhibition.
History
DepositionMar 4, 2020-
Header (metadata) releaseJan 13, 2021-
Map releaseJan 13, 2021-
UpdateJan 13, 2021-
Current statusJan 13, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.008
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  • Surface view colored by cylindrical radius
  • Surface level: 0.008
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  • Surface view with fitted model
  • Atomic models: PDB-6w1m
  • Surface level: 0.008
  • Imaged by UCSF Chimera
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Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21512.png

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Map

FileDownload / File: emd_21512.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotation5HT3A receptor in presence of Ondansetron
Voxel sizeX=Y=Z: 0.848 Å
Density
Contour LevelBy AUTHOR: 0.008 / Movie #1: 0.008
Minimum - Maximum-0.02690947 - 0.058029246
Average (Standard dev.)0.00021393194 (±0.0017154844)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 254.4 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8480.8480.848
M x/y/z300300300
origin x/y/z0.0000.0000.000
length x/y/z254.400254.400254.400
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ400400400
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS300300300
D min/max/mean-0.0270.0580.000

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Supplemental data

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Mask #1

Fileemd_21512_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_21512_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_21512_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Serotonin receptor

EntireName: Serotonin receptor5-HT receptor
Components
  • Complex: Serotonin receptor5-HT receptor
    • Protein or peptide: 5-hydroxytryptamine receptor 3A
  • Ligand: ondansetron

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Supramolecule #1: Serotonin receptor

SupramoleculeName: Serotonin receptor / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mus musculus (house mouse)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
Molecular weightTheoretical: 270 KDa

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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: 52.042121 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: TTQPALLRLS DHLLANYKKG VRPVRDWRKP TTVSIDVIMY AILNVDEKNQ VLTTYIWYRQ YWTDEFLQWT PEDFDNVTKL SIPTDSIWV PDILINEFVD VGKSPNIPYV YVHHRGEVQN YKPLQLVTAC SLDIYNFPFD VQNCSLTFTS WLHTIQDINI T LWRSPEEV ...String:
TTQPALLRLS DHLLANYKKG VRPVRDWRKP TTVSIDVIMY AILNVDEKNQ VLTTYIWYRQ YWTDEFLQWT PEDFDNVTKL SIPTDSIWV PDILINEFVD VGKSPNIPYV YVHHRGEVQN YKPLQLVTAC SLDIYNFPFD VQNCSLTFTS WLHTIQDINI T LWRSPEEV RSDKSIFINQ GEWELLEVFP QFKEFSIDIS NSYAEMKFYV IIRRRPLFYA VSLLLPSIFL MVVDIVGFCL PP DSGERVS FKITLLLGYS VFLIIVSDTL PATAIGTPLI GVYFVVCMAL LVISLAETIF IVRLVHKQDL QRPVPDWLRH LVL DRIAWI LCLGEQPMAH RPPATFQANK TDDCSAMGNH CSHVGGPQDL EKTPRGRGSP LPPPREASLA VRGLLQELSS IRHF LEKRD EMREVARDWL RVGYVLDRLL FRIYLLAVLA YSITLVTLWS IWHYS

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Macromolecule #5: ondansetron

MacromoleculeName: ondansetron / type: ligand / ID: 5 / Number of copies: 5 / Formula: S87
Molecular weightTheoretical: 293.363 Da
Chemical component information

ChemComp-S87:
ondansetron / medication, chemotherapy*YM / Ondansetron

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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

Concentration3 mg/mL
BufferpH: 8
GridModel: Quantifoil R1.2/1.3 / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK I / Details: blot for 2.5 seconds.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal magnification: 105000
Sample stageCooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Frames/image: 1-30 / Number real images: 2530 / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 449628
CTF correctionSoftware - Name: Gctf (ver. 1.06)
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6be1

Initial angle assignmentType: RANDOM ASSIGNMENT / Software - Name: RELION (ver. 3.1)
Final 3D classificationSoftware - Name: RELION (ver. 3.1)
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: RELION (ver. 3.1)
Final reconstructionApplied symmetry - Point group: C5 (5 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.06 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 67333

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: OTHER / Overall B value: 50
Output model

PDB-6w1m:
Cryo-EM structure of 5HT3A receptor in presence of Ondansetron

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