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- EMDB-21511: Cryo-EM structure of 5HT3A receptor in presence of Alosetron -

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Basic information

Entry
Database: EMDB / ID: EMD-21511
TitleCryo-EM structure of 5HT3A receptor in presence of Alosetron
Map data5HT3A receptor in presence of Alosetron
Sample
  • Complex: Serotonin receptor
    • Protein or peptide: 5-hydroxytryptamine receptor 3A
  • Ligand: alosetron
  • Ligand: CHLORIDE ION
KeywordsTRANSPORT 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 / inorganic cation transmembrane transport / excitatory extracellular ligand-gated monoatomic ion channel activity / cleavage furrow / transmembrane transporter complex / extracellular ligand-gated monoatomic ion channel activity ...Neurotransmitter receptors and postsynaptic signal transmission / serotonin-gated monoatomic cation channel activity / serotonin-activated cation-selective channel complex / serotonin receptor signaling pathway / serotonin binding / inorganic cation transmembrane transport / excitatory extracellular ligand-gated monoatomic ion channel activity / cleavage furrow / transmembrane transporter complex / extracellular ligand-gated monoatomic ion channel activity / 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 / transmembrane signaling receptor activity / 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 ...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: 2.92 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-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.008
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.008
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6w1j
  • Surface level: 0.008
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21511.png

Downloads & links

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Map

FileDownload / File: emd_21511.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotation5HT3A receptor in presence of Alosetron
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 300 pix.
= 254.4 Å		0.85 Å/pix.
x 300 pix.
= 254.4 Å		0.85 Å/pix.
x 300 pix.
= 254.4 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.848 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.008 / Movie #1: 0.008
Minimum - Maximum-0.029968334 - 0.070217215
Average (Standard dev.)0.00021246023 (±0.0019827283)
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-0.0300.0700.000

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Supplemental data

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Mask #1

Fileemd_21511_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_21511_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_21511_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Serotonin receptor

EntireName: Serotonin receptor
Components
  • Complex: Serotonin receptor
    • Protein or peptide: 5-hydroxytryptamine receptor 3A
  • Ligand: alosetron
  • Ligand: CHLORIDE ION

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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)
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

UniProtKB: 5-hydroxytryptamine (serotonin) receptor 3A

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Macromolecule #5: alosetron

MacromoleculeName: alosetron / type: ligand / ID: 5 / Number of copies: 5 / Formula: S7Y
Molecular weightTheoretical: 294.351 Da
Chemical component information

ChemComp-S7Y:
alosetron / antagonist*YM

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Macromolecule #6: CHLORIDE ION

MacromoleculeName: CHLORIDE ION / type: ligand / ID: 6 / Number of copies: 1 / Formula: CL
Molecular weightTheoretical: 35.453 Da

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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
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Frames/image: 1-30 / Number real images: 4350 / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal magnification: 105000
Sample stageCooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 568452
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6be1

Final reconstructionApplied symmetry - Point group: C5 (5 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.92 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 42065
Initial angle assignmentType: RANDOM ASSIGNMENT / Software - Name: RELION (ver. 3.1)
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: RELION (ver. 3.1)
Final 3D classificationSoftware - Name: RELION (ver. 3.1)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: OTHER / Overall B value: 30
Output model

PDB-6w1j:
Cryo-EM structure of 5HT3A receptor in presence of Alosetron

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