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- PDB-8ai7: Structure of carbamoylated human butyrylcholinesterase upon react... -

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Basic information

Entry
Database: PDB / ID: 8ai7
TitleStructure of carbamoylated human butyrylcholinesterase upon reaction with 3-(((2-cycloheptylethyl)(methyl)amino)methyl)-1H-indol-7-yl N,N-dimethylcarbamate
ComponentsCholinesterase
KeywordsHYDROLASE / Butyrylcholinesterase / Complex / Inhibitor / Carbamate
Function / homology
Function and homology information


cholinesterase / cocaine metabolic process / neuroblast differentiation / response to folic acid / choline binding / Neurotransmitter clearance / cholinesterase activity / response to alkaloid / choline metabolic process / negative regulation of synaptic transmission ...cholinesterase / cocaine metabolic process / neuroblast differentiation / response to folic acid / choline binding / Neurotransmitter clearance / cholinesterase activity / response to alkaloid / choline metabolic process / negative regulation of synaptic transmission / acetylcholine catabolic process / hydrolase activity, acting on ester bonds / peptide hormone processing / acetylcholinesterase activity / nuclear envelope lumen / Synthesis of PC / Aspirin ADME / 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 / Alpha/Beta hydrolase fold
Similarity search - Domain/homology
Chem-M8X / Cholinesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.13 Å
AuthorsBrazzolotto, X. / Meden, A. / Knez, D. / Gobec, S. / Nachon, F.
Funding support France, 1items
OrganizationGrant numberCountry
French Ministry of Armed ForcesNBC-5-C-4210 France
CitationJournal: Eur.J.Med.Chem. / Year: 2023
Title: Pseudo-irreversible butyrylcholinesterase inhibitors: Structure-activity relationships, computational and crystallographic study of the N-dialkyl O-arylcarbamate warhead.
Authors: Meden, A. / Knez, D. / Brazzolotto, X. / Modeste, F. / Perdih, A. / Pislar, A. / Zorman, M. / Zorovic, M. / Denic, M. / Pajk, S. / Zivin, M. / Nachon, F. / Gobec, S.
History
DepositionJul 25, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 1, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
F: Cholinesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,12823
Polymers59,7851
Non-polymers3,34322
Water3,639202
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5260 Å2
ΔGint-61 kcal/mol
Surface area21630 Å2
MethodPISA
Unit cell
Length a, b, c (Å)154.455, 154.455, 128.280
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
11F-890-

HOH

21F-893-

HOH

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Components

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Protein , 1 types, 1 molecules F

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


Mass: 59784.582 Da / Num. of mol.: 1
Mutation: N17Q, N455Q, N481Q, N486Q enginered 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 , 3 types, 6 molecules

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


Type: oligosaccharide / Mass: 367.349 Da / Num. of mol.: 3
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.: 1
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
#8: 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.: 2 / 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

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Non-polymers , 6 types, 218 molecules

#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#5: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: Cl
#6: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#7: Chemical ChemComp-M8X / 3-[[2-cycloheptylethyl(methyl)amino]methyl]-1~{H}-indol-7-ol


Mass: 300.438 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H28N2O / Feature type: SUBJECT OF INVESTIGATION
#9: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 202 / Source method: isolated from a natural source / Formula: H2O

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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: 3.2 Å3/Da / Density % sol: 61.6 %
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: ID23-1 / Wavelength: 0.8856 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 21, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8856 Å / Relative weight: 1
ReflectionResolution: 2.13→49.34 Å / Num. obs: 42424 / % possible obs: 98.17 % / Redundancy: 6.8 % / Biso Wilson estimate: 51.8 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.08928 / Rpim(I) all: 0.03594 / Rrim(I) all: 0.09654 / Net I/σ(I): 10.97
Reflection shellResolution: 2.13→2.21 Å / Redundancy: 6.9 % / Rmerge(I) obs: 1.659 / Mean I/σ(I) obs: 1.12 / Num. unique obs: 4165 / CC1/2: 0.485 / Rpim(I) all: 0.6663 / Rrim(I) all: 1.794 / % possible all: 97.55

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Processing

Software
NameVersionClassification
Cootmodel building
PHENIX1.20.1_4487refinement
XDSdata reduction
XSCALEdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1p0i

1p0i


Resolution: 2.13→49.34 Å / SU ML: 0.2858 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 24.8646
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2177 2057 4.85 %
Rwork0.1771 40346 -
obs0.179 42403 98.18 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 65.82 Å2
Refinement stepCycle: LAST / Resolution: 2.13→49.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4195 0 212 202 4609
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00814540
X-RAY DIFFRACTIONf_angle_d0.87136164
X-RAY DIFFRACTIONf_chiral_restr0.0674680
X-RAY DIFFRACTIONf_plane_restr0.0066774
X-RAY DIFFRACTIONf_dihedral_angle_d12.9741663
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.13-2.180.42921250.36182630X-RAY DIFFRACTION96.87
2.18-2.240.37391360.31292667X-RAY DIFFRACTION99.29
2.24-2.30.31631260.27022695X-RAY DIFFRACTION98.91
2.3-2.370.28421330.23972666X-RAY DIFFRACTION99.29
2.37-2.440.27661440.22682703X-RAY DIFFRACTION99.1
2.44-2.530.25711490.21012666X-RAY DIFFRACTION98.98
2.53-2.630.24911320.22172690X-RAY DIFFRACTION98.53
2.63-2.750.24621240.21572685X-RAY DIFFRACTION98.73
2.75-2.90.2611350.19372671X-RAY DIFFRACTION98.56
2.9-3.080.20841550.18712690X-RAY DIFFRACTION98.31
3.08-3.320.22941290.18072682X-RAY DIFFRACTION98.25
3.32-3.650.18891370.1622693X-RAY DIFFRACTION97.82
3.65-4.180.18161410.14312704X-RAY DIFFRACTION97.8
4.18-5.260.18481420.13582719X-RAY DIFFRACTION97.25
5.26-49.340.21481490.17472785X-RAY DIFFRACTION95.45
Refinement TLS params.Method: refined / Origin x: 16.8874562071 Å / Origin y: 32.1877996498 Å / Origin z: 38.8961206893 Å
111213212223313233
T0.354953623986 Å2-0.022290395592 Å20.0391399846588 Å2-0.343279629577 Å20.0515228995176 Å2--0.477987741574 Å2
L1.4931732127 °20.312273916533 °2-0.326865508997 °2-1.71342676318 °2-0.254918703052 °2--2.20446481515 °2
S-0.0204432371071 Å °-0.0166158505808 Å °0.155886681155 Å °-0.128143913892 Å °0.0916743346539 Å °0.0364094430412 Å °-0.0839927297604 Å °0.0341815813616 Å °-0.0663826965668 Å °
Refinement TLS groupSelection details: chain 'F'

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