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- PDB-8cgo: Structure of human butyrylcholinesterase in complex with N-{[2-(b... -

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Basic information

Entry
Database: PDB / ID: 8cgo
TitleStructure of human butyrylcholinesterase in complex with N-{[2-(benzyloxy)-3-methoxyphenyl]methyl}-N-[3-(2-fluorophenyl)propyl]cyclobutanamine
ComponentsCholinesterase
KeywordsHYDROLASE / Butyrylcholinesterase / inhibitor / complex.
Function / homology
Function and homology information


cholinesterase / cocaine metabolic process / neuroblast differentiation / Neurotransmitter clearance / cholinesterase activity / choline binding / response to folic acid / response to alkaloid / acetylcholine catabolic process / negative regulation of synaptic transmission ...cholinesterase / cocaine metabolic process / neuroblast differentiation / Neurotransmitter clearance / cholinesterase activity / choline binding / response to folic acid / response to alkaloid / acetylcholine catabolic process / negative regulation of synaptic transmission / peptide hormone processing / acetylcholinesterase activity / choline metabolic process / hydrolase activity, acting on ester bonds / Aspirin ADME / nuclear envelope lumen / Synthesis of PC / Synthesis, secretion, and deacylation of Ghrelin / catalytic activity / response to glucocorticoid / xenobiotic metabolic process / learning / amyloid-beta binding / blood microparticle / negative regulation of cell population proliferation / endoplasmic reticulum lumen / enzyme binding / extracellular space / extracellular region / identical protein binding / plasma membrane
Similarity search - Function
Acetylcholinesterase, tetramerisation domain / Acetylcholinesterase tetramerisation domain / Cholinesterase / Carboxylesterase type B, conserved site / Carboxylesterases type-B signature 2. / Carboxylesterase type B, active site / Carboxylesterases type-B serine active site. / Carboxylesterase, type B / Carboxylesterase family / Alpha/Beta hydrolase fold
Similarity search - Domain/homology
N-acetyl-alpha-neuraminic acid / Chem-XB8 / Cholinesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.65 Å
AuthorsBrazzolotto, X. / Pidany, F. / Korabecny, J. / Cahlikova, L. / Nachon, F.
Funding support France, 1items
OrganizationGrant numberCountry
French Ministry of Armed ForcesNBC-5-C-4120 France
CitationJournal: Eur.J.Med.Chem. / Year: 2023
Title: Highly selective butyrylcholinesterase inhibitors related to Amaryllidaceae alkaloids - Design, synthesis, and biological evaluation.
Authors: Pidany, F. / Kroustkova, J. / Al Mamun, A. / Suchankova, D. / Brazzolotto, X. / Nachon, F. / Chantegreil, F. / Dolezal, R. / Pulkrabkova, L. / Muckova, L. / Hrabinova, M. / Finger, V. / ...Authors: Pidany, F. / Kroustkova, J. / Al Mamun, A. / Suchankova, D. / Brazzolotto, X. / Nachon, F. / Chantegreil, F. / Dolezal, R. / Pulkrabkova, L. / Muckova, L. / Hrabinova, M. / Finger, V. / Kufa, M. / Soukup, O. / Jun, D. / Jenco, J. / Kunes, J. / Novakova, L. / Korabecny, J. / Cahlikova, L.
History
DepositionFeb 6, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 14, 2023Provider: repository / Type: Initial release

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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)63,44615
Polymers59,7141
Non-polymers3,73314
Water1,802100
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4800 Å2
ΔGint-4 kcal/mol
Surface area21550 Å2
Unit cell
Length a, b, c (Å)153.388, 153.388, 126.467
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-797-

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.: 2
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 / N-Acetylglucosamine


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
#7: Sugar ChemComp-SIA / N-acetyl-alpha-neuraminic acid / N-acetylneuraminic acid / sialic acid / alpha-sialic acid / O-SIALIC ACID / 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 , 5 types, 107 molecules

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


Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#6: Chemical ChemComp-XB8 / ~{N}-[3-(2-fluorophenyl)propyl]-~{N}-[(3-methoxy-2-phenylmethoxy-phenyl)methyl]cyclobutanamine


Mass: 433.558 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H32FNO2 / Feature type: SUBJECT OF INVESTIGATION
#8: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#9: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#10: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 100 / 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: 3.11 Å3/Da / Density % sol: 60.51 %
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: BM07 / Wavelength: 0.979507 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 16, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979507 Å / Relative weight: 1
ReflectionResolution: 2.65→76.69 Å / Num. obs: 22244 / % possible obs: 99.9 % / Redundancy: 26.1 % / Biso Wilson estimate: 60.62 Å2 / CC1/2: 0.999 / CC star: 1 / Rmerge(I) obs: 0.1405 / Rpim(I) all: 0.02809 / Rrim(I) all: 0.1433 / Net I/σ(I): 21.57
Reflection shellResolution: 2.65→2.745 Å / Redundancy: 27.3 % / Rmerge(I) obs: 1.729 / Mean I/σ(I) obs: 2.27 / Num. unique obs: 2181 / CC1/2: 0.84 / CC star: 0.956 / Rpim(I) all: 0.3356 / Rrim(I) all: 1.761 / % possible all: 99.95

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Processing

Software
NameVersionClassification
Cootmodel building
PHENIX1.20.1_4487refinement
PHASERphasing
MxCuBEdata collection
autoPROCdata processing
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.65→76.69 Å / SU ML: 0.2858 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.2582
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2155 1107 4.98 %
Rwork0.1776 21137 -
obs0.1795 22244 99.91 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 69.9 Å2
Refinement stepCycle: LAST / Resolution: 2.65→76.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4203 0 243 100 4546
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00874613
X-RAY DIFFRACTIONf_angle_d0.97846276
X-RAY DIFFRACTIONf_chiral_restr0.0549696
X-RAY DIFFRACTIONf_plane_restr0.0074785
X-RAY DIFFRACTIONf_dihedral_angle_d9.1941684
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.65-2.770.31431170.24692616X-RAY DIFFRACTION99.96
2.77-2.910.27481400.23492599X-RAY DIFFRACTION100
2.91-3.10.27651490.2132589X-RAY DIFFRACTION99.96
3.1-3.340.26631430.19252608X-RAY DIFFRACTION100
3.34-3.670.20941270.18022637X-RAY DIFFRACTION99.96
3.67-4.20.23191340.15752646X-RAY DIFFRACTION99.96
4.2-5.290.17621380.14862671X-RAY DIFFRACTION100
5.3-76.690.19071590.17612771X-RAY DIFFRACTION99.46
Refinement TLS params.Method: refined / Origin x: -16.5628762065 Å / Origin y: -31.7533338811 Å / Origin z: -24.8276901071 Å
111213212223313233
T0.397467527456 Å2-0.0489704037035 Å2-0.0290810963452 Å2-0.358131248051 Å2-0.0581679325399 Å2--0.485733596351 Å2
L1.40328769782 °20.239638657109 °20.50117633598 °2-1.48333819062 °2-0.0625573095753 °2--2.16700165357 °2
S-0.0136266595454 Å °0.00287374147489 Å °-0.158215501882 Å °-0.161331026433 Å °0.0730623685319 Å °-0.0376186030151 Å °0.105642924926 Å °-0.048928512495 Å °-0.0472928835818 Å °
Refinement TLS groupSelection details: chain 'A' and (resid 3 through 529 )

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