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Database: PDB / ID: 5k5e
TitleDiscovery and Structure-Activity Relationships of a Highly Selective Butyrylcholinesterase Inhibitor by Structure-Based Virtual Screening
ComponentsCholinesterase
KeywordsHYDROLASE / High selective Inhibitor / Butyrylcholinesterase
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 ...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, catalytic domain / Alpha/Beta hydrolase fold / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-6QS / Cholinesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsDe la Mora, E. / Dighe, S.N. / Deora, G.S. / Ross, B.P. / Nachon, F. / Brazzolotto, X.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Discovery and Structure-Activity Relationships of a Highly Selective Butyrylcholinesterase Inhibitor by Structure-Based Virtual Screening.
Authors: Dighe, S.N. / Deora, G.S. / De la Mora, E. / Nachon, F. / Chan, S. / Parat, M.O. / Brazzolotto, X. / Ross, B.P.
History
DepositionMay 23, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0Jul 27, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 7, 2016Group: Database references
Revision 1.2May 9, 2018Group: Data collection / Source and taxonomy / Category: entity_src_gen / reflns
Item: _entity_src_gen.pdbx_host_org_cell_line / _entity_src_gen.pdbx_host_org_ncbi_taxonomy_id ..._entity_src_gen.pdbx_host_org_cell_line / _entity_src_gen.pdbx_host_org_ncbi_taxonomy_id / _entity_src_gen.pdbx_host_org_scientific_name / _entity_src_gen.pdbx_host_org_vector / _reflns.pdbx_Rmerge_I_obs
Revision 1.3Feb 20, 2019Group: Advisory / Data collection / Derived calculations
Category: pdbx_data_processing_status / pdbx_validate_symm_contact / struct_conn
Revision 1.4Oct 2, 2019Group: Data collection / 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
Item: _pdbx_struct_assembly.details / _pdbx_struct_assembly.method_details
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_unobs_or_zero_occ_atoms / pdbx_validate_close_contact / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.type_symbol / _chem_comp.name / _chem_comp.type / _pdbx_entity_nonpoly.entity_id / _pdbx_entity_nonpoly.name / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_unobs_or_zero_occ_atoms.label_asym_id / _pdbx_validate_close_contact.auth_asym_id_2 / _pdbx_validate_close_contact.auth_seq_id_2 / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Feb 15, 2023Group: Database references / Structure summary / Category: chem_comp / database_2
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 2.2Mar 1, 2023Group: Advisory / Category: pdbx_database_PDB_obs_spr
Revision 2.3Feb 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
A: Cholinesterase
B: Cholinesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)124,14022
Polymers119,3152
Non-polymers4,82520
Water2,288127
1
A: Cholinesterase
hetero molecules

B: Cholinesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)124,14022
Polymers119,3152
Non-polymers4,82520
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_555-x,y+1/2,-z+1/21
Unit cell
Length a, b, c (Å)75.810, 80.070, 230.630
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 59657.402 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BCHE, CHE1 / Cell line (production host): S2 / Production host: Drosophila melanogaster (fruit fly) / References: UniProt: P06276, cholinesterase

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Sugars , 2 types, 13 molecules

#2: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 3 / Source method: obtained synthetically
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}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.: 10 / 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 , 4 types, 134 molecules

#4: Chemical ChemComp-6QS / [(2~{R})-oxolan-2-yl]methyl 4-(9-ethylcarbazol-3-yl)-2-methyl-5-oxidanylidene-4,6,7,8-tetrahydro-1~{H}-quinoline-3-carboxylate


Mass: 484.586 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C30H32N2O4
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: C2H6O2
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C3H8O3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 127 / Source method: isolated from a natural source / Formula: H2O

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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: 2.94 Å3/Da / Density % sol: 58.19 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 7.4
Details: 0.1M Ammonium acetate pH 7.4, 13% Polyethylenglycol 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.97 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 31, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.8→20 Å / Num. obs: 35273 / % possible obs: 99.5 % / Observed criterion σ(I): 2.1 / Redundancy: 4.6 % / Biso Wilson estimate: 65.7 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.091 / Net I/σ(I): 12.8
Reflection shellResolution: 2.8→2.87 Å / Redundancy: 4.8 % / Rmerge(I) obs: 0.68 / Mean I/σ(I) obs: 2.1 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4aqd

4aqd


Resolution: 2.8→19.984 Å / SU ML: 0.35 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 20.88 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2015 3257 4.93 %
Rwork0.1734 --
obs0.1747 35270 99.19 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.8→19.984 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8390 0 320 127 8837
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0169003
X-RAY DIFFRACTIONf_angle_d1.87612260
X-RAY DIFFRACTIONf_dihedral_angle_d20.6213289
X-RAY DIFFRACTIONf_chiral_restr0.1041330
X-RAY DIFFRACTIONf_plane_restr0.0141562
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8-2.84170.35881500.32242741X-RAY DIFFRACTION99
2.8417-2.8860.32581510.28882684X-RAY DIFFRACTION99
2.886-2.93310.32051380.28212780X-RAY DIFFRACTION100
2.9331-2.98350.31321470.25252732X-RAY DIFFRACTION99
2.9835-3.03760.31911200.24592771X-RAY DIFFRACTION100
3.0376-3.09580.23391470.24082712X-RAY DIFFRACTION100
3.0958-3.15880.26591380.23642797X-RAY DIFFRACTION99
3.1588-3.22720.22751700.22572684X-RAY DIFFRACTION99
3.2272-3.30190.2641260.212724X-RAY DIFFRACTION99
3.3019-3.38410.24181400.20182673X-RAY DIFFRACTION99
3.3841-3.47520.24821410.20622757X-RAY DIFFRACTION99
3.4752-3.57690.22551450.17872729X-RAY DIFFRACTION99
3.5769-3.69160.211370.17342738X-RAY DIFFRACTION99
3.6916-3.82270.20841350.16372778X-RAY DIFFRACTION100
3.8227-3.97460.1841480.15482701X-RAY DIFFRACTION99
3.9746-4.1540.16331510.14612711X-RAY DIFFRACTION99
4.154-4.37080.16881350.13752702X-RAY DIFFRACTION98
4.3708-4.64140.1691320.12392768X-RAY DIFFRACTION99
4.6414-4.99460.16141340.13322745X-RAY DIFFRACTION99
4.9946-5.48780.14681510.15982727X-RAY DIFFRACTION100
5.4878-6.26040.18471380.16772729X-RAY DIFFRACTION99
6.2604-7.80840.18961410.17042725X-RAY DIFFRACTION99
7.8084-19.98470.17371420.15192701X-RAY DIFFRACTION98
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.7075-0.24320.64972.3814-0.73683.20330.17210.4288-0.1253-0.1047-0.1587-0.12940.11590.2632-0.01350.40270.0592-0.02020.4355-0.02050.3209-5.17216.393116.6274
22.2674-0.42940.82483.60970.22883.84950.10.0719-0.21380.10580.09270.06120.4064-0.127-0.17820.4425-0.0314-0.020.4127-0.0150.3572-25.8698-30.310744.4069
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A'
2X-RAY DIFFRACTION2chain 'B'

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