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- PDB-7q1n: Crystal structure of human butyrylcholinesterase in complex with ... -

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Basic information

Entry
Database: PDB / ID: 7q1n
TitleCrystal structure of human butyrylcholinesterase in complex with N-[(2R)-3-[(cyclohexylmethyl)amino]-2-hydroxypropyl]-2,2-diphenylacetamide
ComponentsCholinesterase
KeywordsHYDROLASE / Butyrylcholinesterase / Inhibitor / Complex
Function / homology
Function and homology information


cholinesterase / cocaine metabolic process / neuroblast differentiation / Neurotransmitter clearance / choline metabolic process / response to alkaloid / choline binding / response to folic acid / acetylcholine catabolic process / negative regulation of synaptic transmission ...cholinesterase / cocaine metabolic process / neuroblast differentiation / Neurotransmitter clearance / choline metabolic process / response to alkaloid / choline binding / response to folic acid / acetylcholine catabolic process / negative regulation of synaptic transmission / cholinesterase activity / peptide hormone processing / acetylcholinesterase activity / hydrolase activity, acting on ester bonds / nuclear envelope lumen / Aspirin ADME / Synthesis of PC / Synthesis, secretion, and deacylation of Ghrelin / catalytic activity / 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-8IV / GLYCOLIC ACID / Cholinesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.35 Å
AuthorsBrazzolotto, X. / Panek, D. / Pasieka, A. / Malawska, B. / Nachon, F.
Funding support France, 1items
OrganizationGrant numberCountry
French Ministry of Armed ForcesNBC-5-C-4210 France
CitationJournal: Eur.J.Med.Chem. / Year: 2023
Title: Discovery of new, highly potent and selective inhibitors of BuChE - design, synthesis, in vitro and in vivo evaluation and crystallography studies.
Authors: Panek, D. / Pasieka, A. / Latacz, G. / Zareba, P. / Szczech, M. / Godyn, J. / Chantegreil, F. / Nachon, F. / Brazzolotto, X. / Skrzypczak-Wiercioch, A. / Walczak, M. / Smolik, M. / Salat, K. ...Authors: Panek, D. / Pasieka, A. / Latacz, G. / Zareba, P. / Szczech, M. / Godyn, J. / Chantegreil, F. / Nachon, F. / Brazzolotto, X. / Skrzypczak-Wiercioch, A. / Walczak, M. / Smolik, M. / Salat, K. / Hofner, G. / Wanner, K. / Wieckowska, A. / Malawska, B.
History
DepositionOct 20, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 16, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 1, 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.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Feb 8, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / chem_comp_atom / chem_comp_bond
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _atom_site_anisotrop.pdbx_auth_atom_id / _atom_site_anisotrop.pdbx_label_atom_id
Revision 2.1Feb 7, 2024Group: Refinement description / Category: 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,67129
Polymers59,7141
Non-polymers3,95728
Water2,702150
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6570 Å2
ΔGint-113 kcal/mol
Surface area21460 Å2
Unit cell
Length a, b, c (Å)154.260, 154.260, 127.830
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-623-

NA

21A-839-

HOH

31A-849-

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 , 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-ROHGlycam 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
[][D-1-deoxy-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.: 3
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4[LFucpa1-6]DGlcpNAcb1-ROHGlycam 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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}[(6+1)][a-L-Fucp]{}}LINUCSPDB-CARE
#5: 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

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Non-polymers , 7 types, 172 molecules

#4: Chemical ChemComp-8IV / N-[(2R)-3-(cyclohexylmethylamino)-2-oxidanyl-propyl]-2,2-diphenyl-ethanamide / N-[(2R)-3-[(cyclohexylmethyl)amino]-2-hydroxypropyl]-2,2-diphenylacetamide


Mass: 380.523 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H32N2O2 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#7: Chemical ChemComp-GOA / GLYCOLIC ACID / HYDROXYACETIC ACID / HYDROXYETHANOIC ACID / Glycolic acid


Mass: 76.051 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C2H4O3
#8: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


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


Mass: 35.453 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: Cl
#10: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#11: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 150 / 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: 3.18 Å3/Da / Density % sol: 61.37 %
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: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.9786 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Nov 12, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9786 Å / Relative weight: 1
ReflectionResolution: 2.354→109.1 Å / Num. obs: 31957 / % possible obs: 99.12 % / Redundancy: 26.8 % / Biso Wilson estimate: 58.61 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.1635 / Rpim(I) all: 0.03226 / Rrim(I) all: 0.1667 / Net I/σ(I): 14.06
Reflection shellResolution: 2.354→2.438 Å / Redundancy: 25.2 % / Rmerge(I) obs: 2.438 / Mean I/σ(I) obs: 1.37 / Num. unique obs: 2942 / CC1/2: 0.615 / Rpim(I) all: 0.4791 / Rrim(I) all: 2.486 / % possible all: 91.56

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
XDSdata reduction
XSCALEdata scaling
Cootmodel building
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1p0i

1p0i


Resolution: 2.35→109.1 Å / SU ML: 0.2953 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 26.2247
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2261 1594 5 %
Rwork0.1762 30311 -
obs0.1787 31905 99.14 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 73.77 Å2
Refinement stepCycle: LAST / Resolution: 2.35→109.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4199 0 241 150 4590
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00814605
X-RAY DIFFRACTIONf_angle_d0.91966259
X-RAY DIFFRACTIONf_chiral_restr0.0554697
X-RAY DIFFRACTIONf_plane_restr0.0069788
X-RAY DIFFRACTIONf_dihedral_angle_d13.3936690
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.35-2.430.34631300.29792502X-RAY DIFFRACTION90.79
2.43-2.520.31811420.27842711X-RAY DIFFRACTION100
2.52-2.620.31381440.26142737X-RAY DIFFRACTION100
2.62-2.740.26611450.22322753X-RAY DIFFRACTION99.97
2.74-2.880.25731450.19762746X-RAY DIFFRACTION99.97
2.88-3.060.21661440.1982745X-RAY DIFFRACTION100
3.06-3.30.24141460.19622772X-RAY DIFFRACTION99.97
3.3-3.630.25711470.17132781X-RAY DIFFRACTION100
3.63-4.150.22261460.14842784X-RAY DIFFRACTION99.97
4.15-5.230.17141490.13832833X-RAY DIFFRACTION100
5.23-49.210.21721560.17322947X-RAY DIFFRACTION99.84
Refinement TLS params.Method: refined / Origin x: 16.8681108024 Å / Origin y: 32.1367068534 Å / Origin z: 38.6568978787 Å
111213212223313233
T0.383536351913 Å2-0.0412523010798 Å20.02708739412 Å2-0.36782650521 Å20.0578778879964 Å2--0.534883100675 Å2
L1.46200365028 °20.234727332333 °2-0.558112300209 °2-1.72275432959 °2-0.224935938184 °2--2.70742525655 °2
S-0.0102243366044 Å °-0.00758535864646 Å °0.138418734704 Å °-0.163128413065 Å °0.0841818435588 Å °0.0200853965371 Å °-0.109110031689 Å °0.0333792246805 Å °-0.0648452218278 Å °
Refinement TLS groupSelection details: chain A

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