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- PDB-7qhd: Human Butyrylcholinesterase in complex with (S)-1-(4-((2-(1H-indo... -

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Basic information

Entry
Database: PDB / ID: 7qhd
TitleHuman Butyrylcholinesterase in complex with (S)-1-(4-((2-(1H-indol-3-yl)ethyl)carbamoyl)benzyl)-N-(3-((1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)piperidine-3-carboxamide
ComponentsCholinesterase
KeywordsHYDROLASE / Butyrylcholinesterase / Inhibitor / Complex
Function / homology
Function and homology information


cholinesterase / : / neuroblast differentiation / response to folic acid / choline binding / Neurotransmitter clearance / cholinesterase activity / response to alkaloid / choline metabolic process / acetylcholine catabolic process ...cholinesterase / : / neuroblast differentiation / response to folic acid / choline binding / Neurotransmitter clearance / cholinesterase activity / response to alkaloid / choline metabolic process / acetylcholine catabolic process / negative regulation of synaptic transmission / peptide hormone processing / hydrolase activity, acting on ester bonds / acetylcholinesterase activity / Aspirin ADME / Synthesis of PC / nuclear envelope lumen / catalytic activity / Synthesis, secretion, and deacylation of Ghrelin / xenobiotic metabolic process / response to glucocorticoid / learning / amyloid-beta binding / blood microparticle / endoplasmic reticulum lumen / negative regulation of cell population proliferation / enzyme binding / extracellular space / extracellular region / identical protein binding / plasma membrane
Similarity search - Function
Acetylcholinesterase, tetramerisation domain / Acetylcholinesterase tetramerisation domain / : / Cholinesterase / Carboxylesterase type B, active site / Carboxylesterases type-B serine active site. / Carboxylesterase type B, conserved site / Carboxylesterases type-B signature 2. / Carboxylesterase, type B / Carboxylesterase family ...Acetylcholinesterase, tetramerisation domain / Acetylcholinesterase tetramerisation domain / : / Cholinesterase / Carboxylesterase type B, active site / Carboxylesterases type-B serine active site. / Carboxylesterase type B, conserved site / Carboxylesterases type-B signature 2. / Carboxylesterase, type B / Carboxylesterase family / Alpha/Beta hydrolase fold, catalytic domain / Alpha/Beta hydrolase fold / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-C0I / N-acetyl-alpha-neuraminic acid / Cholinesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.04 Å
AuthorsBrazzolotto, X. / Jing, L. / Zhan, P. / Liu, X. / Nachon, F.
Funding support France, 1items
OrganizationGrant numberCountry
French Ministry of Armed ForcesNBC-5-C-4210 France
CitationJournal: Bioorg.Chem. / Year: 2023
Title: Rapid discovery and crystallography study of highly potent and selective butylcholinesterase inhibitors based on oxime-containing libraries and conformational restriction strategies.
Authors: Jing, L. / Wei, W. / Meng, B. / Chantegreil, F. / Nachon, F. / Martinez, A. / Wu, G. / Zhao, H. / Song, Y. / Kang, D. / Brazzolotto, X. / Zhan, P. / Liu, X.
History
DepositionDec 12, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 21, 2022Provider: repository / Type: Initial release
Revision 1.1Jul 5, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Nov 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

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Assembly

Deposited unit
A: Cholinesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,12626
Polymers59,7141
Non-polymers4,41225
Water5,278293
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6010 Å2
ΔGint-58 kcal/mol
Surface area21820 Å2
MethodPISA
Unit cell
Length a, b, c (Å)154.520, 154.520, 127.505
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number97
Space group name H-MI422
Space group name HallI42
Symmetry operation#1: x,y,z
#2: -y,x,z
#3: y,-x,z
#4: x,-y,-z
#5: -x,y,-z
#6: -x,-y,z
#7: y,x,-z
#8: -y,-x,-z
#9: x+1/2,y+1/2,z+1/2
#10: -y+1/2,x+1/2,z+1/2
#11: y+1/2,-x+1/2,z+1/2
#12: x+1/2,-y+1/2,-z+1/2
#13: -x+1/2,y+1/2,-z+1/2
#14: -x+1/2,-y+1/2,z+1/2
#15: y+1/2,x+1/2,-z+1/2
#16: -y+1/2,-x+1/2,-z+1/2
Components on special symmetry positions
IDModelComponents
11A-971-

HOH

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Cholinesterase / Acylcholine acylhydrolase / Butyrylcholine esterase / Choline esterase II / Pseudocholinesterase


Mass: 59713.512 Da / Num. of mol.: 1
Mutation: N17Q, N455Q, N481Q, N486Q mutations compared to mature wild type sequence to avoid too much N-glycozylation. Numeration on the maturated enzyme (devoid of the signal peptide)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BCHE, CHE1 / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P06276, cholinesterase

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Sugars , 4 types, 7 molecules

#2: Polysaccharide alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 367.349 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
LFucpa1-6DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,2,1/[a2122h-1b_1-5_2*NCC/3=O][a1221m-1a_1-5]/1-2/a6-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(6+1)][a-L-Fucp]{}}}LINUCSPDB-CARE
#3: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta- ...2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 570.542 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4[LFucpa1-6]DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1221m-1a_1-5]/1-1-2/a4-b1_a6-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}[(6+1)][a-L-Fucp]{}}}LINUCSPDB-CARE
#4: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#8: Sugar ChemComp-SIA / N-acetyl-alpha-neuraminic acid / N-acetylneuraminic acid / sialic acid / alpha-sialic acid / O-SIALIC ACID


Type: D-saccharide, alpha linking / Mass: 309.270 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H19NO9
IdentifierTypeProgram
DNeup5AcaCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-a-D-neuraminic acidCOMMON NAMEGMML 1.0
a-D-Neup5AcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
Neu5AcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 6 types, 311 molecules

#5: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID


Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#6: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C3H8O3
#7: Chemical ChemComp-C0I / (3~{S})-1-[[4-[2-(1~{H}-indol-3-yl)ethylcarbamoyl]phenyl]methyl]-~{N}-[3-(1,2,3,4-tetrahydroacridin-9-ylamino)propyl]piperidine-3-carboxamide


Mass: 642.832 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C40H46N6O2 / Feature type: SUBJECT OF INVESTIGATION
#9: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#10: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: Cl
#11: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 293 / 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: 3.19 Å3/Da / Density % sol: 61.4 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: Ammonium Sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.979184 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Nov 13, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979184 Å / Relative weight: 1
ReflectionResolution: 2.04→77.26 Å / Num. obs: 48566 / % possible obs: 98.16 % / Redundancy: 6.9 % / Biso Wilson estimate: 37.86 Å2 / CC1/2: 0.999 / CC star: 1 / Rmerge(I) obs: 0.06498 / Rpim(I) all: 0.02574 / Rrim(I) all: 0.07013 / Net I/σ(I): 16.23
Reflection shellResolution: 2.04→2.113 Å / Redundancy: 6.8 % / Rmerge(I) obs: 0.7103 / Mean I/σ(I) obs: 2.4 / Num. unique obs: 4792 / CC1/2: 0.796 / CC star: 0.941 / Rpim(I) all: 0.2867 / Rrim(I) all: 0.7684 / % possible all: 99.3

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Processing

Software
NameVersionClassification
Cootmodel building
PHENIX1.19.2_4158refinement
MxCuBEdata collection
autoPROCdata processing
PHASERphasing
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1p0i

1p0i


Resolution: 2.04→77.26 Å / SU ML: 0.2256 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 20.6766
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2044 2422 4.99 %
Rwork0.1713 46144 -
obs0.1729 48566 98.18 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 45.92 Å2
Refinement stepCycle: LAST / Resolution: 2.04→77.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4203 0 280 295 4778
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00824630
X-RAY DIFFRACTIONf_angle_d0.87956292
X-RAY DIFFRACTIONf_chiral_restr0.0554689
X-RAY DIFFRACTIONf_plane_restr0.0074784
X-RAY DIFFRACTIONf_dihedral_angle_d14.9084690
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.04-2.080.31861350.27582717X-RAY DIFFRACTION99.41
2.08-2.120.32321390.24182693X-RAY DIFFRACTION99.12
2.12-2.170.24411360.21072708X-RAY DIFFRACTION99.13
2.17-2.230.25751290.1962743X-RAY DIFFRACTION99.34
2.23-2.290.24221370.18452693X-RAY DIFFRACTION98.95
2.29-2.350.2371430.17642715X-RAY DIFFRACTION99.2
2.35-2.430.24361470.1842708X-RAY DIFFRACTION99.17
2.43-2.520.22041400.18452692X-RAY DIFFRACTION98.44
2.52-2.620.22181470.1882704X-RAY DIFFRACTION98.55
2.62-2.740.22141410.18432722X-RAY DIFFRACTION98.62
2.74-2.880.22651490.17872708X-RAY DIFFRACTION98.25
2.88-3.060.22171500.17112678X-RAY DIFFRACTION98.06
3.06-3.30.1841400.17352718X-RAY DIFFRACTION97.94
3.3-3.630.18841320.16342729X-RAY DIFFRACTION97.58
3.63-4.150.16411740.14172678X-RAY DIFFRACTION97.07
4.15-5.230.15591380.14182739X-RAY DIFFRACTION96.32
5.23-77.260.23081450.18222799X-RAY DIFFRACTION94.42
Refinement TLS params.Method: refined / Origin x: 16.9808877912 Å / Origin y: 32.1835069911 Å / Origin z: 38.5677705179 Å
111213212223313233
T0.268008518879 Å2-0.0190476944897 Å20.0163692090611 Å2-0.27133027195 Å20.0356245791181 Å2--0.292106523215 Å2
L1.05045980434 °20.0728007955548 °2-0.3071041615 °2-1.3161115554 °2-0.0774887493721 °2--1.3763242306 °2
S0.0116950612226 Å °0.0105737585957 Å °0.0795690009093 Å °-0.104992386208 Å °0.0469971009708 Å °0.0215366797642 Å °-0.0568961596123 Å °0.00420139368818 Å °-0.058106600884 Å °
Refinement TLS groupSelection details: chain 'A'

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