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- EMDB-29410: Full-length mouse 5-HT3A receptor in complex with SMP100, pre-act... -

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Basic information

Entry
Database: EMDB / ID: EMD-29410
TitleFull-length mouse 5-HT3A receptor in complex with SMP100, pre-activated
Map data
Sample
  • Complex: 5-HT3A pentamer in complex with orthosteric ligand SMP100
    • Protein or peptide: 5-hydroxytryptamine receptor 3A
  • Ligand: 5-[(1R,3S,4R)-1-azabicyclo[2.2.2]octan-3-yl]-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indazol-6-one
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsPartial agonist / cys-loop / pLGIC / ion channel / 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 / inorganic cation transmembrane transport / excitatory extracellular ligand-gated monoatomic ion channel activity / 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 / inorganic cation transmembrane transport / excitatory extracellular ligand-gated monoatomic ion 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 ...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: 2.7 Å
AuthorsFelt KC / Chakrapani S
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM134896 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM134896-2S1 United States
CitationJournal: Nat Struct Mol Biol / Year: 2024
Title: Structural basis for partial agonism in 5-HT receptors.
Authors: Kevin Felt / Madeleine Stauffer / Leslie Salas-Estrada / Peter R Guzzo / Dejian Xie / Jinkun Huang / Marta Filizola / Sudha Chakrapani /
Abstract: Hyperactivity of serotonin 3 receptors (5-HTR) underlies pathologies associated with irritable bowel syndrome and chemotherapy-induced nausea and vomiting. Setrons, a class of high-affinity ...Hyperactivity of serotonin 3 receptors (5-HTR) underlies pathologies associated with irritable bowel syndrome and chemotherapy-induced nausea and vomiting. Setrons, a class of high-affinity competitive antagonists, are used in the treatment of these conditions. Although generally effective for chemotherapy-induced nausea and vomiting, the use of setrons for treating irritable bowel syndrome has been impaired by adverse side effects. Partial agonists are now being considered as an alternative strategy, with potentially less severe side effects than full antagonists. However, a structural understanding of how these ligands work is lacking. Here, we present high-resolution cryogenic electron microscopy structures of the mouse 5-HTR in complex with partial agonists (SMP-100 and ALB-148471) captured in pre-activated and open-like conformational states. Molecular dynamics simulations were used to assess the stability of drug-binding poses and interactions with the receptor over time. Together, these studies reveal mechanisms for the functional differences between orthosteric partial agonists, full agonists and antagonists of the 5-HTR.
History
DepositionJan 9, 2023-
Header (metadata) releaseDec 27, 2023-
Map releaseDec 27, 2023-
UpdateMay 1, 2024-
Current statusMay 1, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29410.png

Downloads & links

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Map

FileDownload / File: emd_29410.map.gz / Format: CCP4 / Size: 59.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 250 pix.
= 275. Å		1.1 Å/pix.
x 250 pix.
= 275. Å		1.1 Å/pix.
x 250 pix.
= 275. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.1 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0157
Minimum - Maximum-0.027419902 - 0.095589444
Average (Standard dev.)0.0004054428 (±0.002819174)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions250250250
Spacing250250250
CellA=B=C: 275.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_29410_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_29410_half_map_2.map
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Sample components

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Entire : 5-HT3A pentamer in complex with orthosteric ligand SMP100

EntireName: 5-HT3A pentamer in complex with orthosteric ligand SMP100
Components
  • Complex: 5-HT3A pentamer in complex with orthosteric ligand SMP100
    • Protein or peptide: 5-hydroxytryptamine receptor 3A
  • Ligand: 5-[(1R,3S,4R)-1-azabicyclo[2.2.2]octan-3-yl]-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indazol-6-one
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: 5-HT3A pentamer in complex with orthosteric ligand SMP100

SupramoleculeName: 5-HT3A pentamer in complex with orthosteric ligand SMP100
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 331 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: 62.349812 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: WSHPQFEKGG GSGGGSGGGS WSHPQFEKGG GSGGGSGGGS WSHPQFEKGG GSGGGSGGGS WSHPQFEKEN LYFQGATQAR DTTQPALLR LSDHLLANYK KGVRPVRDWR KPTTVSIDVI MYAILNVDEK NQVLTTYIWY RQYWTDEFLQ WTPEDFDNVT K LSIPTDSI ...String:
WSHPQFEKGG GSGGGSGGGS WSHPQFEKGG GSGGGSGGGS WSHPQFEKGG GSGGGSGGGS WSHPQFEKEN LYFQGATQAR DTTQPALLR LSDHLLANYK KGVRPVRDWR KPTTVSIDVI MYAILNVDEK NQVLTTYIWY RQYWTDEFLQ WTPEDFDNVT K LSIPTDSI WVPDILINEF VDVGKSPNIP YVYVHHRGEV QNYKPLQLVT ACSLDIYNFP FDVQNCSLTF TSWLHTIQDI NI TLWRSPE EVRSDKSIFI NQGEWELLEV FPQFKEFSID ISNSYAEMKF YVIIRRRPLF YAVSLLLPSI FLMVVDIVGF CLP PDSGER VSFKITLLLG YSVFLIIVSD TLPATAIGTP LIGVYFVVCM ALLVISLAET IFIVRLVHKQ DLQRPVPDWL RHLV LDRIA WILCLGEQPM AHRPPATFQA NKTDDCSGSD LLPAMGNHCS HVGGPQDLEK TPRGRGSPLP PPREASLAVR GLLQE LSSI RHFLEKRDEM REVARDWLRV GYVLDRLLFR IYLLAVLAYS ITLVTLWSIW HYSENLYFQG TETSQVAPA

UniProtKB: 5-hydroxytryptamine receptor 3A

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Macromolecule #2: 5-[(1R,3S,4R)-1-azabicyclo[2.2.2]octan-3-yl]-1,3,4,5-tetrahydro-6...

MacromoleculeName: 5-[(1R,3S,4R)-1-azabicyclo[2.2.2]octan-3-yl]-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indazol-6-one
type: ligand / ID: 2 / Number of copies: 5 / Formula: Y82
Molecular weightTheoretical: 296.367 Da
Chemical component information

ChemComp-Y82:
5-[(1R,3S,4R)-1-azabicyclo[2.2.2]octan-3-yl]-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indazol-6-one

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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: 15 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

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

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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

Concentration2.6 mg/mL
BufferpH: 8
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK I

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 81000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

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

6np0

Final reconstructionApplied symmetry - Point group: C5 (5 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 191788
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)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL
Output model

PDB-8frx:
Full-length mouse 5-HT3A receptor in complex with SMP100, pre-activated

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