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- PDB-7um4: Crystal structure of inactive 5-HT5AR in complex with AS2674723 -

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Basic information

Entry
Database: PDB / ID: 7um4
TitleCrystal structure of inactive 5-HT5AR in complex with AS2674723
Components
  • 5-hydroxytryptamine receptor 5A
  • PGS
KeywordsMEMBRANE PROTEIN / GPCR / inactive state / 5-HT5AR / HTR5A
Function / homology
Function and homology information


Gi/o-coupled serotonin receptor activity / Serotonin receptors / serotonin receptor activity / G protein-coupled serotonin receptor activity / neurotransmitter receptor activity / postsynaptic specialization membrane / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / adenylate cyclase-inhibiting serotonin receptor signaling pathway / hippocampus development / adenylate cyclase-activating G protein-coupled receptor signaling pathway ...Gi/o-coupled serotonin receptor activity / Serotonin receptors / serotonin receptor activity / G protein-coupled serotonin receptor activity / neurotransmitter receptor activity / postsynaptic specialization membrane / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / adenylate cyclase-inhibiting serotonin receptor signaling pathway / hippocampus development / adenylate cyclase-activating G protein-coupled receptor signaling pathway / response to estradiol / G alpha (i) signalling events / perikaryon / chemical synaptic transmission / G protein-coupled receptor signaling pathway / dendrite / plasma membrane
Similarity search - Function
5-Hydroxytryptamine 5A receptor / 5-hydroxytryptamine receptor family / Rhopdopsin 7-helix transmembrane proteins / Rhodopsin 7-helix transmembrane proteins / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-NN6 / DI(HYDROXYETHYL)ETHER / TRIETHYLENE GLYCOL / 5-hydroxytryptamine receptor 5A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsZhang, S. / Roth, B.L.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)RO1MH112205 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)U24DK1169195 United States
CitationJournal: Nat Struct Mol Biol / Year: 2022
Title: Inactive and active state structures template selective tools for the human 5-HT receptor.
Authors: Shicheng Zhang / He Chen / Chengwei Zhang / Ying Yang / Petr Popov / Jing Liu / Brian E Krumm / Can Cao / Kuglae Kim / Yan Xiong / Vsevolod Katritch / Brian K Shoichet / Jian Jin / Jonathan ...Authors: Shicheng Zhang / He Chen / Chengwei Zhang / Ying Yang / Petr Popov / Jing Liu / Brian E Krumm / Can Cao / Kuglae Kim / Yan Xiong / Vsevolod Katritch / Brian K Shoichet / Jian Jin / Jonathan F Fay / Bryan L Roth /
Abstract: Serotonin receptors are important targets for established therapeutics and drug development as they are expressed throughout the human body and play key roles in cell signaling. There are 12 ...Serotonin receptors are important targets for established therapeutics and drug development as they are expressed throughout the human body and play key roles in cell signaling. There are 12 serotonergic G protein-coupled receptor members encoded in the human genome, of which the 5-hydroxytryptamine (5-HT) receptor (5-HTR) is the least understood and lacks selective tool compounds. Here, we report four high-resolution (2.73-2.80 Å) structures of human 5-HTRs, including an inactive state structure bound to an antagonist AS2674723 by crystallization and active state structures bound to a partial agonist lisuride and two full agonists, 5-carboxamidotryptamine (5-CT) and methylergometrine, by cryo-EM. Leveraging the new structures, we developed a highly selective and potent antagonist for 5-HTR. Collectively, these findings both enhance our understanding of this enigmatic receptor and provide a roadmap for structure-based drug discovery for 5-HTR.
History
DepositionApr 6, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 20, 2022Provider: repository / Type: Initial release
Revision 1.1Jul 27, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: 5-hydroxytryptamine receptor 5A
B: PGS
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,5239
Polymers60,2562
Non-polymers1,2677
Water1448
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)135.289, 42.460, 94.787
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein 5-hydroxytryptamine receptor 5A / 5-HT-5 / 5-HT-5A / 5-HT5A / Serotonin receptor 5A


Mass: 38004.398 Da / Num. of mol.: 1 / Mutation: D65N, I278A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HTR5A / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P47898
#2: Protein PGS


Mass: 22251.660 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)

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Non-polymers , 6 types, 15 molecules

#3: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL


Mass: 150.173 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O4
#4: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C4H10O3
#5: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#6: Chemical ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400


Mass: 238.278 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H22O6 / Comment: precipitant*YM
#7: Chemical ChemComp-NN6 / ~{N}-[azanyl(azanylidene)methylidene]-5-fluoranyl-8-[2,4,6-tris(fluoranyl)phenyl]-3,4-dihydro-1~{H}-isoquinoline-2-carboxamide


Mass: 366.313 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H14F4N4O / Feature type: SUBJECT OF INVESTIGATION
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 8 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.26 Å3/Da / Density % sol: 45.55 %
Crystal growTemperature: 293 K / Method: lipidic cubic phase
Details: 0.1 M Sodium chloride, 0.1 M Lithium sulfate, 0.1 M DL-Malic acid pH 5.9, 30 % v/v PEG 400

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.033 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Aug 13, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033 Å / Relative weight: 1
ReflectionResolution: 2.8→50 Å / Num. obs: 13732 / % possible obs: 99.2 % / Redundancy: 6.6 % / Biso Wilson estimate: 68.7 Å2 / Rmerge(I) obs: 0.307 / Rpim(I) all: 0.122 / Rrim(I) all: 0.332 / Χ2: 0.897 / Net I/σ(I): 5.8
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.8-2.93.61.02412850.5540.5811.1850.58997.2
2.9-3.024.71.01613590.5340.5011.1390.60898.8
3.02-3.155.30.96213300.7050.4491.0660.68899.3
3.15-3.326.40.92713500.5790.3921.0110.71999.5
3.32-3.5370.68513700.7920.280.743199.9
3.53-3.87.70.50513790.8760.1960.5441.035100
3.8-4.187.40.35713730.9180.140.3850.89699.7
4.18-4.797.70.28513750.940.110.3061.0999.8
4.79-6.037.90.25514230.9490.0970.2740.92699.6
6.03-507.40.20514880.960.0790.2210.98898

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
HKL-3000data scaling
PDB_EXTRACT3.27data extraction
HKL-3000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4S0V, 4IAR

4s0v

4iar


Resolution: 2.8→44.73 Å / SU ML: 0.46 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 31.13 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2712 680 4.96 %
Rwork0.2289 13018 -
obs0.2311 13698 97.39 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 143.5 Å2 / Biso mean: 67.5536 Å2 / Biso min: 40.18 Å2
Refinement stepCycle: final / Resolution: 2.8→44.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3536 0 86 8 3630
Biso mean--68.7 56.53 -
Num. residues----453
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 5

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.8-3.020.36681300.31252319244989
3.02-3.320.34351290.2672598272799
3.32-3.80.3121320.248826482780100
3.8-4.790.23211520.210226512803100
4.79-44.730.25221370.20892802293999

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