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- PDB-6i0b: Human butyrylcholinesterase in complex with the S enantiomer of a... -

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Basic information

Entry
Database: PDB / ID: 6i0b
TitleHuman butyrylcholinesterase in complex with the S enantiomer of a chlorotacrine-tryptophan multi-target inhibitor.
ComponentsCholinesterase
KeywordsHYDROLASE / butyrylcholinesterase / multi-target inhibitor
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, catalytic domain ...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-9A5 / Cholinesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.384 Å
AuthorsBrazzolotto, X. / Nachon, F.
Funding support France, 1items
OrganizationGrant numberCountry
French Ministry of Armed ForcesPDH-2-NRBC-3-3201 France
CitationJournal: Eur.J.Med.Chem. / Year: 2019
Title: Novel tacrine-tryptophan hybrids: Multi-target directed ligands as potential treatment for Alzheimer's disease.
Authors: Chalupova, K. / Korabecny, J. / Bartolini, M. / Monti, B. / Lamba, D. / Caliandro, R. / Pesaresi, A. / Brazzolotto, X. / Gastellier, A.J. / Nachon, F. / Pejchal, J. / Jarosova, M. / ...Authors: Chalupova, K. / Korabecny, J. / Bartolini, M. / Monti, B. / Lamba, D. / Caliandro, R. / Pesaresi, A. / Brazzolotto, X. / Gastellier, A.J. / Nachon, F. / Pejchal, J. / Jarosova, M. / Hepnarova, V. / Jun, D. / Hrabinova, M. / Dolezal, R. / Zdarova Karasova, J. / Mzik, M. / Kristofikova, Z. / Misik, J. / Muckova, L. / Jost, P. / Soukup, O. / Benkova, M. / Setnicka, V. / Habartova, L. / Chvojkova, M. / Kleteckova, L. / Vales, K. / Mezeiova, E. / Uliassi, E. / Valis, M. / Nepovimova, E. / Bolognesi, M.L. / Kuca, K.
History
DepositionOct 25, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 27, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 14, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Aug 21, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Jul 8, 2020Group: Data collection / Category: chem_comp / Item: _chem_comp.type
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Refinement description / 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 / software / 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 / _pdbx_struct_assembly_gen.asym_id_list / _software.name / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Jan 24, 2024Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)63,29517
Polymers59,7141
Non-polymers3,58116
Water2,054114
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4540 Å2
ΔGint-11 kcal/mol
Surface area21720 Å2
MethodPISA
Unit cell
Length a, b, c (Å)154.351, 154.351, 128.039
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number97
Space group name H-MI422
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 / ...Acylcholine acylhydrolase / Butyrylcholine esterase / Choline esterase II / Pseudocholinesterase / butyrylcholinesterase


Mass: 59713.512 Da / Num. of mol.: 1 / Mutation: N17Q, N455Q, N481Q, N486Q
Source method: isolated from a genetically manipulated source
Details: (NAG) are N-acetylglucosamine(FUC) are fucose / 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.: 1
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: obtained synthetically
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.: 3 / 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, 124 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-9A5 / (2~{S})-2-azanyl-~{N}-[6-[(6-chloranyl-1,2,3,4-tetrahydroacridin-9-yl)amino]hexyl]-3-(1~{H}-indol-3-yl)propanamide


Mass: 518.093 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H36ClN5O / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: C3H8O3
#8: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#9: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#10: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 114 / 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: 3.1 Å3/Da / Density % sol: 60.38 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: MES pH 6.5 Ammonium Sulphate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.976 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Jul 13, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.384→55.221 Å / Num. obs: 31033 / % possible obs: 99.86 % / Redundancy: 8.2 % / Biso Wilson estimate: 50.88 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.07364 / Rpim(I) all: 0.02706 / Rrim(I) all: 0.07865 / Net I/σ(I): 18.02
Reflection shellResolution: 2.384→2.469 Å / Redundancy: 8 % / Rmerge(I) obs: 0.788 / Mean I/σ(I) obs: 2.56 / Num. unique obs: 3046 / CC1/2: 0.834 / Rpim(I) all: 0.2951 / Rrim(I) all: 0.8434 / % possible all: 99.9

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Processing

Software
NameClassification
PHENIXrefinement
autoPROCdata collection
Aimlessdata scaling
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1p0i

1p0i


Resolution: 2.384→55.221 Å / SU ML: 0.31 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 27.73
RfactorNum. reflection% reflection
Rfree0.2439 1583 5.1 %
Rwork0.1892 --
obs0.192 31033 99.87 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.384→55.221 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4191 0 230 114 4535
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.014587
X-RAY DIFFRACTIONf_angle_d1.0486253
X-RAY DIFFRACTIONf_dihedral_angle_d12.0543633
X-RAY DIFFRACTIONf_chiral_restr0.056681
X-RAY DIFFRACTIONf_plane_restr0.006783
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3838-2.46080.37621230.27692637X-RAY DIFFRACTION100
2.4608-2.54870.35421340.25192657X-RAY DIFFRACTION100
2.5487-2.65080.3041330.23562656X-RAY DIFFRACTION100
2.6508-2.77140.31071470.22492638X-RAY DIFFRACTION100
2.7714-2.91750.2971570.21422625X-RAY DIFFRACTION100
2.9175-3.10030.27681450.20812649X-RAY DIFFRACTION100
3.1003-3.33970.25561350.20532695X-RAY DIFFRACTION100
3.3397-3.67570.241520.18912657X-RAY DIFFRACTION100
3.6757-4.20740.19221290.16432712X-RAY DIFFRACTION100
4.2074-5.30020.20081530.15562708X-RAY DIFFRACTION100
5.3002-55.23560.24031750.18452816X-RAY DIFFRACTION99

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