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- PDB-7voe: Crystal structure of 5-HT2AR in complex with aripiprazole -

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Basic information

Entry
Database: PDB / ID: 7voe
TitleCrystal structure of 5-HT2AR in complex with aripiprazole
Components5-hydroxytryptamine receptor 2A,Soluble cytochrome b562
KeywordsMEMBRANE PROTEIN / GPCR / Dopamine Receptor / serotonin receptor / aripiprazole / antipsychotic
Function / homology
Function and homology information


positive regulation of heat generation / protein localization to cytoskeleton / 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding / Gq/11-coupled serotonin receptor activity / phospholipase C-activating serotonin receptor signaling pathway / positive regulation of phosphatidylinositol biosynthetic process / G protein-coupled serotonin receptor signaling pathway / G protein-coupled serotonin receptor complex / neurofilament / sensitization ...positive regulation of heat generation / protein localization to cytoskeleton / 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding / Gq/11-coupled serotonin receptor activity / phospholipase C-activating serotonin receptor signaling pathway / positive regulation of phosphatidylinositol biosynthetic process / G protein-coupled serotonin receptor signaling pathway / G protein-coupled serotonin receptor complex / neurofilament / sensitization / positive regulation of cytokine production involved in immune response / Serotonin receptors / cell body fiber / artery smooth muscle contraction / serotonin receptor signaling pathway / urinary bladder smooth muscle contraction / serotonin binding / negative regulation of synaptic transmission, glutamatergic / G protein-coupled serotonin receptor activity / positive regulation of platelet aggregation / neurotransmitter receptor activity / positive regulation of DNA biosynthetic process / temperature homeostasis / protein tyrosine kinase activator activity / regulation of dopamine secretion / negative regulation of potassium ion transport / positive regulation of execution phase of apoptosis / detection of temperature stimulus involved in sensory perception of pain / behavioral response to cocaine / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / positive regulation of fat cell differentiation / detection of mechanical stimulus involved in sensory perception of pain / positive regulation of vasoconstriction / release of sequestered calcium ion into cytosol / presynaptic modulation of chemical synaptic transmission / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of glycolytic process / dendritic shaft / glycolytic process / electron transport chain / caveola / memory / positive regulation of inflammatory response / intracellular calcium ion homeostasis / positive regulation of neuron apoptotic process / positive regulation of peptidyl-tyrosine phosphorylation / virus receptor activity / presynaptic membrane / positive regulation of cytosolic calcium ion concentration / cytoplasmic vesicle / chemical synaptic transmission / G alpha (q) signalling events / postsynaptic membrane / periplasmic space / positive regulation of ERK1 and ERK2 cascade / electron transfer activity / iron ion binding / response to xenobiotic stimulus / axon / neuronal cell body / glutamatergic synapse / dendrite / positive regulation of cell population proliferation / heme binding / protein-containing complex binding / identical protein binding / plasma membrane
Similarity search - Function
5-Hydroxytryptamine 2A receptor / 5-hydroxytryptamine receptor family / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Serpentine type 7TM GPCR chemoreceptor Srsx / 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)
Similarity search - Domain/homology
Chem-9SC / CHOLESTEROL / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / Soluble cytochrome b562 / 5-hydroxytryptamine receptor 2A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsChen, Z. / Fan, L. / Wang, H. / Yu, J. / Lu, D. / Qi, J. / Nie, F. / Luo, Z. / Liu, Z. / Cheng, J. / Wang, S.
Funding support China, 3items
OrganizationGrant numberCountry
Chinese Academy of SciencesXDB19020111 China
Ministry of Science and Technology (MoST, China)2020YFA0509600 China
National Natural Science Foundation of China (NSFC)32071197 China
CitationJournal: Nat.Neurosci. / Year: 2022
Title: Structure-based design of a novel third-generation antipsychotic drug lead with potential antidepressant properties.
Authors: Chen, Z. / Fan, L. / Wang, H. / Yu, J. / Lu, D. / Qi, J. / Nie, F. / Luo, Z. / Liu, Z. / Cheng, J. / Wang, S.
History
DepositionOct 13, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 22, 2021Provider: repository / Type: Initial release
Revision 1.1Dec 29, 2021Group: Data collection / Structure summary / Category: diffrn / entity / Item: _diffrn.ambient_temp / _entity.pdbx_mutation
Revision 1.2Feb 16, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.3Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

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Assembly

Deposited unit
A: 5-hydroxytryptamine receptor 2A,Soluble cytochrome b562
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,25511
Polymers41,9581
Non-polymers3,29710
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area390 Å2
ΔGint1 kcal/mol
Surface area17800 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.270, 54.280, 179.550
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21221
Components on special symmetry positions
IDModelComponents
11A-1710-

MG

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Components

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Protein , 1 types, 1 molecules A

#1: Protein 5-hydroxytryptamine receptor 2A,Soluble cytochrome b562 / 5-HT-2 / 5-HT-2A / Serotonin receptor 2A / Cytochrome b-562


Mass: 41958.074 Da / Num. of mol.: 1 / Mutation: S162K,N164W,M1007W,R1098I,H1102I,R1106G,S372N
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HTR2A, HTR2, cybC / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P28223, UniProt: P0ABE7

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Non-polymers , 5 types, 10 molecules

#2: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C27H46O
#3: Chemical ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400


Mass: 238.278 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H22O6 / Comment: precipitant*YM
#4: Chemical
ChemComp-OLC / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / 1-Oleoyl-R-glycerol


Mass: 356.540 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H40O4
#5: Chemical ChemComp-9SC / 7-[4-[4-[2,3-bis(chloranyl)phenyl]piperazin-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-one / Aripiprazole


Mass: 448.385 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H27Cl2N3O2 / Feature type: SUBJECT OF INVESTIGATION / Comment: antipsychotic*YM
#6: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg

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Details

Has ligand of interestY

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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: 2.92 Å3/Da / Density % sol: 57.86 %
Crystal growTemperature: 293.15 K / Method: lipidic cubic phase
Details: 100 mM Tris/HCl, 50 mM ammonium floride, 28%-30% PEG400, 300 mM NDSB-195 or 3% w/v trimethylamine N-oxide dihydrate
PH range: 7.5-8.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL45XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 6, 2020
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.9→48.41 Å / Num. obs: 11410 / % possible obs: 98.9 % / Redundancy: 53.6 % / CC1/2: 0.998 / Rmerge(I) obs: 0.258 / Rpim(I) all: 0.03 / Rrim(I) all: 0.26 / Net I/σ(I): 13.4
Reflection shellResolution: 2.9→3.08 Å / Redundancy: 9.7 % / Rmerge(I) obs: 1.526 / Mean I/σ(I) obs: 1.3 / Num. unique obs: 1712 / CC1/2: 0.65 / Rpim(I) all: 0.443 / Rrim(I) all: 1.593 / % possible all: 94.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6A93

6a93


Resolution: 2.9→48.41 Å / Cor.coef. Fo:Fc: 0.919 / Cor.coef. Fo:Fc free: 0.946 / SU B: 20.267 / SU ML: 0.347 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.376 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2437 589 5.2 %RANDOM
Rwork0.2227 ---
obs0.2237 10783 98.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 212.44 Å2 / Biso mean: 70.901 Å2 / Biso min: 9.85 Å2
Baniso -1Baniso -2Baniso -3
1-1.51 Å20 Å20 Å2
2--5.22 Å2-0 Å2
3----6.73 Å2
Refinement stepCycle: final / Resolution: 2.9→48.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2718 0 201 0 2919
Biso mean--104.43 --
Num. residues----356
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0132976
X-RAY DIFFRACTIONr_bond_other_d0.0010.0173006
X-RAY DIFFRACTIONr_angle_refined_deg1.6851.6184039
X-RAY DIFFRACTIONr_angle_other_deg1.3651.5636896
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1495351
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.19723.214112
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.03915461
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.808156
X-RAY DIFFRACTIONr_chiral_restr0.0760.2419
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.023157
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02631
X-RAY DIFFRACTIONr_mcbond_it7.2297.0921419
X-RAY DIFFRACTIONr_mcbond_other7.237.091418
X-RAY DIFFRACTIONr_mcangle_it10.66410.6291765
LS refinement shellResolution: 2.9→2.975 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.331 47 -
Rwork0.371 713 -
all-760 -
obs--90.69 %

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