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- PDB-7qhe: Human Butyrylcholinesterase in complex with (S)-1-(4-((naphthalen... -

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Basic information

Entry
Database: PDB / ID: 7qhe
TitleHuman Butyrylcholinesterase in complex with (S)-1-(4-((naphthalen-1-yl)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 / cocaine metabolic process / neuroblast differentiation / Neurotransmitter clearance / cholinesterase activity / choline binding / response to folic acid / acetylcholine catabolic process / response to alkaloid / peptide hormone processing ...cholinesterase / cocaine metabolic process / neuroblast differentiation / Neurotransmitter clearance / cholinesterase activity / choline binding / response to folic acid / acetylcholine catabolic process / response to alkaloid / peptide hormone processing / negative regulation of synaptic transmission / choline metabolic process / hydrolase activity, acting on ester bonds / acetylcholinesterase activity / Aspirin ADME / nuclear envelope lumen / Synthesis of PC / catalytic activity / Synthesis, secretion, and deacylation of Ghrelin / 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
Chem-C4I / Cholinesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.47 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 20, 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: Cholinesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,18920
Polymers59,7141
Non-polymers3,47519
Water2,396133
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)154.505, 154.505, 127.520
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

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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 , 2 types, 6 molecules

#2: 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
#3: 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.: 4 / 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, 146 molecules

#4: 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
#5: Chemical ChemComp-C4I / (3~{S})-1-[[4-(naphthalen-1-ylcarbamoyl)phenyl]methyl]-~{N}-[3-(1,2,3,4-tetrahydroacridin-9-ylamino)propyl]piperidine-3-carboxamide


Mass: 625.802 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C40H43N5O2 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


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


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


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


Mass: 18.015 Da / Num. of mol.: 133 / 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: 2.47→55.07 Å / Num. obs: 27052 / % possible obs: 97.23 % / Redundancy: 5.2 % / Biso Wilson estimate: 48.39 Å2 / CC1/2: 0.997 / CC star: 0.999 / Rmerge(I) obs: 0.08995 / Rpim(I) all: 0.04264 / Rrim(I) all: 0.09988 / Net I/σ(I): 13.39
Reflection shellResolution: 2.47→2.562 Å / Redundancy: 5.4 % / Rmerge(I) obs: 0.6839 / Mean I/σ(I) obs: 2.38 / Num. unique obs: 2679 / CC1/2: 0.788 / CC star: 0.939 / Rpim(I) all: 0.3184 / Rrim(I) all: 0.7568 / % possible all: 98.46

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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: 2.47→55.07 Å / SU ML: 0.238 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 24.3446
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2236 1298 4.8 %
Rwork0.1776 25751 -
obs0.1799 27049 97.24 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 56.79 Å2
Refinement stepCycle: LAST / Resolution: 2.47→55.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4203 0 219 133 4555
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0084586
X-RAY DIFFRACTIONf_angle_d0.91556238
X-RAY DIFFRACTIONf_chiral_restr0.0566680
X-RAY DIFFRACTIONf_plane_restr0.0069785
X-RAY DIFFRACTIONf_dihedral_angle_d8.8429674
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.47-2.570.26751510.22752846X-RAY DIFFRACTION98.59
2.57-2.690.33681280.24092857X-RAY DIFFRACTION98.22
2.69-2.830.30751230.22342862X-RAY DIFFRACTION98.16
2.83-3.010.28651320.20942868X-RAY DIFFRACTION98.14
3.01-3.240.23841640.20732847X-RAY DIFFRACTION97.79
3.24-3.570.24491440.1842830X-RAY DIFFRACTION97.28
3.57-4.080.1821530.1482864X-RAY DIFFRACTION96.98
4.08-5.140.17531650.13812838X-RAY DIFFRACTION96.22
5.14-55.070.22991380.17862939X-RAY DIFFRACTION94.07
Refinement TLS params.Method: refined / Origin x: 16.716919361 Å / Origin y: 32.41175408 Å / Origin z: 38.7892111977 Å
111213212223313233
T0.300202447405 Å2-0.0257796047187 Å20.0194605290235 Å2-0.284474369632 Å20.0528924019058 Å2--0.374726605061 Å2
L1.29075500909 °20.272736666029 °2-0.330924518573 °2-1.3991005801 °2-0.0718508005736 °2--2.07223044448 °2
S-0.0279218123632 Å °0.011089266573 Å °0.142599445967 Å °-0.133894906051 Å °0.0545421610079 Å °0.036762856148 Å °-0.112456073589 Å °0.0201364572027 Å °-0.0309322029108 Å °
Refinement TLS groupSelection details: chain 'A'

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