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- PDB-8jt8: Crystal structure of 5-HT2AR in complex with (R)-IHCH-7179 -

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Basic information

Entry
Database: PDB / ID: 8jt8
TitleCrystal structure of 5-HT2AR in complex with (R)-IHCH-7179
Components5-hydroxytryptamine receptor 2A,Soluble cytochrome b562
KeywordsMEMBRANE PROTEIN / GPCR / serotonin receptor / 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 / positive regulation of cytokine production involved in immune response ...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 / positive regulation of cytokine production involved in immune response / artery smooth muscle contraction / Serotonin receptors / cell body fiber / serotonin receptor signaling pathway / sensitization / 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 / temperature homeostasis / positive regulation of DNA biosynthetic process / regulation of dopamine secretion / protein tyrosine kinase activator activity / positive regulation of execution phase of apoptosis / negative regulation of potassium ion transport / 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 / release of sequestered calcium ion into cytosol / positive regulation of vasoconstriction / presynaptic modulation of chemical synaptic transmission / positive regulation of glycolytic process / phosphatidylinositol 3-kinase/protein kinase B signal transduction / dendritic shaft / caveola / glycolytic process / electron transport chain / memory / intracellular calcium ion homeostasis / positive regulation of inflammatory response / positive regulation of peptidyl-tyrosine phosphorylation / positive regulation of neuron apoptotic process / presynaptic membrane / phospholipase C-activating G protein-coupled receptor signaling pathway / virus receptor activity / positive regulation of cytosolic calcium ion concentration / cytoplasmic vesicle / G alpha (q) signalling events / chemical synaptic transmission / postsynaptic membrane / periplasmic space / electron transfer activity / positive regulation of ERK1 and ERK2 cascade / response to xenobiotic stimulus / iron ion binding / axon / neuronal cell body / glutamatergic synapse / dendrite / heme binding / positive regulation of cell population proliferation / 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
CHOLESTEROL / : / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / DI(HYDROXYETHYL)ETHER / Soluble cytochrome b562 / 5-hydroxytryptamine receptor 2A
Similarity search - Component
Biological speciesHomo sapiens (human)
Escherichia coli (E. coli)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsChen, Z. / Fan, L. / Wang, S.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82225025 China
CitationJournal: Cell / Year: 2024
Title: Flexible scaffold-based cheminformatics approach for polypharmacological drug design.
Authors: Zhangcheng Chen / Jing Yu / Huan Wang / Peiyu Xu / Luyu Fan / Fengxiu Sun / Sijie Huang / Pei Zhang / He Huang / Shuo Gu / Bowen Zhang / Yue Zhou / Xiaobo Wan / Gang Pei / H Eric Xu / ...Authors: Zhangcheng Chen / Jing Yu / Huan Wang / Peiyu Xu / Luyu Fan / Fengxiu Sun / Sijie Huang / Pei Zhang / He Huang / Shuo Gu / Bowen Zhang / Yue Zhou / Xiaobo Wan / Gang Pei / H Eric Xu / Jianjun Cheng / Sheng Wang /
Abstract: Effective treatments for complex central nervous system (CNS) disorders require drugs with polypharmacology and multifunctionality, yet designing such drugs remains a challenge. Here, we present a ...Effective treatments for complex central nervous system (CNS) disorders require drugs with polypharmacology and multifunctionality, yet designing such drugs remains a challenge. Here, we present a flexible scaffold-based cheminformatics approach (FSCA) for the rational design of polypharmacological drugs. FSCA involves fitting a flexible scaffold to different receptors using different binding poses, as exemplified by IHCH-7179, which adopted a "bending-down" binding pose at 5-HTR to act as an antagonist and a "stretching-up" binding pose at 5-HTR to function as an agonist. IHCH-7179 demonstrated promising results in alleviating cognitive deficits and psychoactive symptoms in mice by blocking 5-HTR for psychoactive symptoms and activating 5-HTR to alleviate cognitive deficits. By analyzing aminergic receptor structures, we identified two featured motifs, the "agonist filter" and "conformation shaper," which determine ligand binding pose and predict activity at aminergic receptors. With these motifs, FSCA can be applied to the design of polypharmacological ligands at other receptors.
History
DepositionJun 21, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Feb 28, 2024Provider: repository / Type: Initial release
Revision 1.1Apr 10, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2May 8, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)46,07915
Polymers41,9581
Non-polymers4,12114
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area880 Å2
ΔGint0 kcal/mol
Surface area17530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.890, 54.030, 177.840
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,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,M164W,M1007W,R1098I,H1102I,R1106G,S372N
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Escherichia coli (E. coli)
Gene: HTR2A, HTR2, cybC / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P28223, UniProt: P0ABE7

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Non-polymers , 6 types, 14 molecules

#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-EZX / 1-(4-fluorophenyl)-4-[(7R)-2,5,11-triazatetracyclo[7.6.1.0^2,7.0^12,16]hexadeca-1(15),9,12(16),13-tetraen-5-yl]butan-1-one


Mass: 377.455 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H24FN3O / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-OLC / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / 1-Oleoyl-R-glycerol


Mass: 356.540 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C21H40O4
#5: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46O
#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-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O3

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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: 2.8 Å3/Da / Density % sol: 56.06 %
Crystal growTemperature: 293.15 K / Method: lipidic cubic phase / pH: 8
Details: 100 mM Tris/HCl, 160 mM Potassium fluoride, 30% 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: Jul 20, 2022
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→48.89 Å / Num. obs: 13075 / % possible obs: 96 % / Redundancy: 25.8 % / CC1/2: 0.997 / Rpim(I) all: 0.068 / Net I/σ(I): 7.9
Reflection shellResolution: 2.7→2.83 Å / Redundancy: 19.2 % / Mean I/σ(I) obs: 1.3 / Num. unique obs: 1418 / CC1/2: 0.351 / Rpim(I) all: 0.55 / % possible all: 78

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.7→47.19 Å / Cor.coef. Fo:Fc: 0.907 / Cor.coef. Fo:Fc free: 0.926 / SU B: 21.179 / SU ML: 0.391 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 1.428 / ESU R Free: 0.365 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2698 632 4.8 %RANDOM
Rwork0.2477 ---
obs0.2489 12403 96.04 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 169.25 Å2 / Biso mean: 64.423 Å2 / Biso min: 20.41 Å2
Baniso -1Baniso -2Baniso -3
1-2.28 Å20 Å20 Å2
2--3.06 Å2-0 Å2
3----5.34 Å2
Refinement stepCycle: final / Resolution: 2.7→47.19 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2720 0 210 0 2930
Biso mean--91.3 --
Num. residues----355
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0132985
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172979
X-RAY DIFFRACTIONr_angle_refined_deg1.7431.6194035
X-RAY DIFFRACTIONr_angle_other_deg1.5331.5636843
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.275352
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.67323.796108
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.99115464
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.109156
X-RAY DIFFRACTIONr_chiral_restr0.0840.2413
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.023151
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02629
X-RAY DIFFRACTIONr_mcbond_it6.4546.5581417
X-RAY DIFFRACTIONr_mcbond_other6.4526.5561416
X-RAY DIFFRACTIONr_mcangle_it9.3479.8491766
LS refinement shellResolution: 2.7→2.77 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.262 29 -
Rwork0.348 691 -
all-720 -
obs--77.09 %

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