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- PDB-7aiy: Crystal structure of human butyrylcholinesterase in complex with ... -

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Entry
Database: PDB / ID: 7aiy
TitleCrystal structure of human butyrylcholinesterase in complex with 2-{1-[4-(12-Amino-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)butyl]-1H-1,2,3-triazol-4-yl}-N-[4-hydroxy-3-methoxybenzyl]acetamide
ComponentsCholinesterase
KeywordsHYDROLASE / human butyrylcholinesterase / AD / alzheimer disease
Function / homology
Function and homology information


cholinesterase / cocaine metabolic process / neuroblast differentiation / choline binding / Neurotransmitter clearance / cholinesterase activity / choline metabolic process / negative regulation of synaptic transmission / response to folic acid / acetylcholine catabolic process ...cholinesterase / cocaine metabolic process / neuroblast differentiation / choline binding / Neurotransmitter clearance / cholinesterase activity / choline metabolic process / negative regulation of synaptic transmission / response to folic acid / acetylcholine catabolic process / response to alkaloid / 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 / response to glucocorticoid / xenobiotic metabolic process / 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, 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-8U2 / Cholinesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.937 Å
AuthorsCoquelle, N. / Colletier, J.P.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice.
Authors: Viayna, E. / Coquelle, N. / Cieslikiewicz-Bouet, M. / Cisternas, P. / Oliva, C.A. / Sanchez-Lopez, E. / Ettcheto, M. / Bartolini, M. / De Simone, A. / Ricchini, M. / Rendina, M. / Pons, M. / ...Authors: Viayna, E. / Coquelle, N. / Cieslikiewicz-Bouet, M. / Cisternas, P. / Oliva, C.A. / Sanchez-Lopez, E. / Ettcheto, M. / Bartolini, M. / De Simone, A. / Ricchini, M. / Rendina, M. / Pons, M. / Firuzi, O. / Perez, B. / Saso, L. / Andrisano, V. / Nachon, F. / Brazzolotto, X. / Garcia, M.L. / Camins, A. / Silman, I. / Jean, L. / Inestrosa, N.C. / Colletier, J.P. / Renard, P.Y. / Munoz-Torrero, D.
History
DepositionSep 28, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 6, 2021Provider: repository / Type: Initial release
Revision 1.1May 4, 2022Group: 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 1.2Oct 26, 2022Group: Derived calculations
Category: pdbx_struct_assembly / pdbx_struct_assembly_gen ...pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / pdbx_struct_oper_list
Revision 1.3Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.4Nov 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
B: Cholinesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)137,5673
Polymers136,9772
Non-polymers5891
Water00
1
A: Cholinesterase
hetero molecules

A: Cholinesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)138,1564
Polymers136,9772
Non-polymers1,1782
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation1
2
B: Cholinesterase

A: Cholinesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)137,5673
Polymers136,9772
Non-polymers5891
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation1
Unit cell
Length a, b, c (Å)73.878, 79.318, 228.710
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 68488.727 Da / Num. of mol.: 2
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
#2: Chemical ChemComp-8U2 / 2-{1-[4-(12-Amino-3-chloro-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinolin-9-yl)butyl]-1H-1,2,3-triazol-4-yl}-N-[4-hydroxy-3-methoxybenzyl]acetamide


Mass: 589.128 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H37ClN6O3 / Feature type: SUBJECT OF INVESTIGATION
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: 2.45 Å3/Da / Density % sol: 49.71 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.4
Details: 250 mM ammonium acetate 20% polyethylene glycol 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-3 / Wavelength: 0.9679 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Nov 4, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9679 Å / Relative weight: 1
ReflectionResolution: 2.937→50 Å / Num. obs: 26966 / % possible obs: 91.5 % / Redundancy: 4.6 % / CC1/2: 0.993 / Rmerge(I) obs: 0.143 / Net I/σ(I): 9.1
Reflection shellResolution: 2.937→3.11 Å / Rmerge(I) obs: 0.0119 / Mean I/σ(I) obs: 1 / Num. unique obs: 3621 / CC1/2: 0.405

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Processing

Software
NameVersionClassification
PHENIX1.10.1_2155refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4tpk

4tpk


Resolution: 2.937→48.874 Å / SU ML: 0.46 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 31.36 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.3005 1356 5.04 %
Rwork0.225 25568 -
obs0.2287 26924 91.31 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 143.76 Å2 / Biso mean: 75.979 Å2 / Biso min: 30 Å2
Refinement stepCycle: final / Resolution: 2.937→48.874 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8384 0 42 0 8426
Biso mean--77.56 --
Num. residues----1054
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0148769
X-RAY DIFFRACTIONf_angle_d1.62711935
X-RAY DIFFRACTIONf_chiral_restr0.1381258
X-RAY DIFFRACTIONf_plane_restr0.0091549
X-RAY DIFFRACTIONf_dihedral_angle_d19.5845174
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.9372-3.04220.40431230.3403211278
3.0422-3.1640.41871210.3137231684
3.164-3.30790.32821220.2757244589
3.3079-3.48230.33681280.2659253592
3.4823-3.70040.31891520.24259694
3.7004-3.9860.27741360.2201270897
3.986-4.38690.30841450.1911266295
4.3869-5.02110.24951380.1817266495
5.0211-6.3240.29561430.221273796
6.324-48.8740.28581480.2192279393

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