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- PDB-7wc8: Crystal structure of serotonin 2A receptor in complex with lumate... -

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Basic information

Entry
Database: PDB / ID: 7wc8
TitleCrystal structure of serotonin 2A receptor in complex with lumateperone
Components5-hydroxytryptamine receptor 2A,5-hydroxytryptamine receptor 2A,Soluble cytochrome b562
KeywordsMEMBRANE PROTEIN / serotonin 2A receptor / serotonin / 5-HT / Lumateperone
Function / homology
Function and homology information


protein localization to cytoskeleton / positive regulation of heat generation / 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding / Gq/11-coupled serotonin receptor activity / positive regulation of phosphatidylinositol biosynthetic process / G protein-coupled serotonin receptor signaling pathway / G protein-coupled serotonin receptor complex / neurofilament / cell body fiber / phospholipase C-activating serotonin receptor signaling pathway ...protein localization to cytoskeleton / positive regulation of heat generation / 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding / Gq/11-coupled serotonin receptor activity / positive regulation of phosphatidylinositol biosynthetic process / G protein-coupled serotonin receptor signaling pathway / G protein-coupled serotonin receptor complex / neurofilament / cell body fiber / phospholipase C-activating serotonin receptor signaling pathway / artery smooth muscle contraction / Serotonin receptors / serotonin receptor activity / positive regulation of cytokine production involved in immune response / G protein-coupled serotonin receptor activity / sensitization / serotonin receptor signaling pathway / neurotransmitter receptor activity / urinary bladder smooth muscle contraction / serotonin binding / positive regulation of platelet aggregation / negative regulation of synaptic transmission, glutamatergic / positive regulation of DNA biosynthetic process / temperature homeostasis / positive regulation of vasoconstriction / detection of temperature stimulus involved in sensory perception of pain / regulation of dopamine secretion / negative regulation of potassium ion transport / protein tyrosine kinase activator activity / positive regulation of execution phase of apoptosis / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / detection of mechanical stimulus involved in sensory perception of pain / positive regulation of fat cell differentiation / behavioral response to cocaine / release of sequestered calcium ion into cytosol / presynaptic modulation of chemical synaptic transmission / positive regulation of glycolytic process / dendritic shaft / glycolytic process / caveola / memory / intracellular calcium ion homeostasis / positive regulation of inflammatory response / positive regulation of neuron apoptotic process / positive regulation of cytosolic calcium ion concentration / presynaptic membrane / virus receptor activity / cytoplasmic vesicle / G alpha (q) signalling events / chemical synaptic transmission / postsynaptic membrane / positive regulation of ERK1 and ERK2 cascade / response to xenobiotic stimulus / axon / neuronal cell body / positive regulation of cell population proliferation / dendrite / protein-containing complex binding / glutamatergic synapse / identical protein binding / plasma membrane
Similarity search - Function
5-Hydroxytryptamine 2A receptor / 5-hydroxytryptamine receptor family / Cytochrome c/b562 / Serpentine type 7TM GPCR chemoreceptor Srsx / Four Helix Bundle (Hemerythrin (Met), subunit A) / 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) ...5-Hydroxytryptamine 2A receptor / 5-hydroxytryptamine receptor family / Cytochrome c/b562 / Serpentine type 7TM GPCR chemoreceptor Srsx / Four Helix Bundle (Hemerythrin (Met), subunit A) / 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-92S / CHOLESTEROL / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / DI(HYDROXYETHYL)ETHER / 5-hydroxytryptamine receptor 2A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.45 Å
AuthorsCao, D. / Yu, J. / Wang, H. / Luo, Z. / Liu, X. / He, L. / Qi, J. / Fan, L. / Tang, L. / Chen, Z. ...Cao, D. / Yu, J. / Wang, H. / Luo, Z. / Liu, X. / He, L. / Qi, J. / Fan, L. / Tang, L. / Chen, Z. / Li, J. / Cheng, J. / Wang, S.
Funding support China, 3items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2020YFA0509600 China
National Natural Science Foundation of China (NSFC)32071197 China
Chinese Academy of SciencesXDB19020111 China
CitationJournal: Science / Year: 2022
Title: Structure-based discovery of nonhallucinogenic psychedelic analogs.
Authors: Cao, D. / Yu, J. / Wang, H. / Luo, Z. / Liu, X. / He, L. / Qi, J. / Fan, L. / Tang, L. / Chen, Z. / Li, J. / Cheng, J. / Wang, S.
History
DepositionDec 18, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 26, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 16, 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 5, 2022Group: Structure summary / Category: chem_comp / Item: _chem_comp.pdbx_synonyms
Revision 1.3Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.4Nov 13, 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)48,28720
Polymers42,0561
Non-polymers6,23119
Water1448
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area450 Å2
ΔGint-1 kcal/mol
Surface area18930 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.470, 55.330, 179.970
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-1201-

MG

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 42056.258 Da / Num. of mol.: 1 / Mutation: S162K,M164W,M1007W,R1098I,H1102I,R1106G,S372N
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HTR2A, HTR2, HTR2A, cybC / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P28223

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Non-polymers , 7 types, 27 molecules

#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#3: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H46O
#4: Chemical ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400


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


Mass: 356.540 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: C21H40O4
#6: Chemical ChemComp-92S / 1-(4-fluorophenyl)-4-[(10~{R},15~{S})-4-methyl-1,4,12-triazatetracyclo[7.6.1.0^{5,16}.0^{10,15}]hexadeca-5,7,9(16)-trien-12-yl]butan-1-one / lumateperone


Mass: 393.497 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H28FN3O / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#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: 2.93 Å3/Da / Density % sol: 58 %
Crystal growTemperature: 293.15 K / Method: lipidic cubic phase / pH: 8
Details: 100 mM Tris-HCl, 160 mM Potassium fluoride, 30% (v/v) PEG400

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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: Feb 3, 2021
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.45→47.7 Å / Num. obs: 18848 / % possible obs: 99.3 % / Redundancy: 25.3 % / CC1/2: 0.988 / Net I/σ(I): 10.8
Reflection shellResolution: 2.45→2.54 Å / Redundancy: 6.6 % / Mean I/σ(I) obs: 1.1 / Num. unique obs: 1967 / CC1/2: 0.422 / % possible all: 94.1

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6A93

6a93


Resolution: 2.45→47.7 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.952 / SU B: 9.957 / SU ML: 0.217 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.422 / ESU R Free: 0.256 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2438 913 4.9 %RANDOM
Rwork0.2185 ---
obs0.2197 17888 99.29 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 201.03 Å2 / Biso mean: 76.097 Å2 / Biso min: 35.39 Å2
Baniso -1Baniso -2Baniso -3
1-1.46 Å2-0 Å2-0 Å2
2--2.19 Å2-0 Å2
3----3.64 Å2
Refinement stepCycle: final / Resolution: 2.45→47.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2798 0 346 8 3152
Biso mean--113.02 72.52 -
Num. residues----360
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0133204
X-RAY DIFFRACTIONr_bond_other_d0.0020.0173284
X-RAY DIFFRACTIONr_angle_refined_deg1.571.6254317
X-RAY DIFFRACTIONr_angle_other_deg1.4251.5637580
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2745357
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.12123.279122
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.56215496
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.202156
X-RAY DIFFRACTIONr_chiral_restr0.0840.2441
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.023286
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02654
X-RAY DIFFRACTIONr_mcbond_it7.8297.3491437
X-RAY DIFFRACTIONr_mcbond_other7.827.3481436
X-RAY DIFFRACTIONr_mcangle_it9.7511.0551791
LS refinement shellResolution: 2.45→2.514 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.367 56 -
Rwork0.339 1193 -
all-1249 -
obs--90.57 %

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