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

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Basic information

Entry
Database: PDB / ID: 7awg
TitleCrystal structure of human butyrylcholinesterase in complex with (2-((1-(benzenesulfonyl)-1H-indol-4-yl)oxy)ethyl)(benzyl)amine
ComponentsCholinesterase
KeywordsHYDROLASE / butyrylcholinesterase / inhibitor complex
Function / homology
Function and homology information


cholinesterase / : / neuroblast differentiation / response to folic acid / choline binding / Neurotransmitter clearance / cholinesterase activity / choline metabolic process / response to alkaloid / acetylcholine catabolic process ...cholinesterase / : / neuroblast differentiation / response to folic acid / choline binding / Neurotransmitter clearance / cholinesterase activity / choline metabolic process / response to alkaloid / acetylcholine catabolic process / negative regulation of synaptic transmission / peptide hormone processing / hydrolase activity, acting on ester bonds / acetylcholinesterase activity / Aspirin ADME / Synthesis of PC / nuclear envelope lumen / catalytic activity / Synthesis, secretion, and deacylation of Ghrelin / xenobiotic metabolic process / response to glucocorticoid / 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, active site / Carboxylesterases type-B serine active site. / Carboxylesterase type B, conserved site / Carboxylesterases type-B signature 2. / Carboxylesterase, type B / Carboxylesterase family / Alpha/Beta hydrolase fold
Similarity search - Domain/homology
Chem-S6Q / N-acetyl-alpha-neuraminic acid / Cholinesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsBrazzolotto, X. / Wichur, T. / Wieckowska, A.
Funding support France, 1items
OrganizationGrant numberCountry
French Ministry of Armed ForcesNBC-5-4210 France
CitationJournal: Eur.J.Med.Chem. / Year: 2021
Title: Development and crystallography-aided SAR studies of multifunctional BuChE inhibitors and 5-HT 6 R antagonists with beta-amyloid anti-aggregation properties.
Authors: Wichur, T. / Godyn, J. / Goral, I. / Latacz, G. / Bucki, A. / Siwek, A. / Gluch-Lutwin, M. / Mordyl, B. / Sniecikowska, J. / Walczak, M. / Knez, D. / Jukic, M. / Salat, K. / Gobec, S. / ...Authors: Wichur, T. / Godyn, J. / Goral, I. / Latacz, G. / Bucki, A. / Siwek, A. / Gluch-Lutwin, M. / Mordyl, B. / Sniecikowska, J. / Walczak, M. / Knez, D. / Jukic, M. / Salat, K. / Gobec, S. / Kolaczkowski, M. / Malawska, B. / Brazzolotto, X. / Wieckowska, A.
History
DepositionNov 8, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 29, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 6, 2021Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
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_PubMed / _citation.title / _citation.year
Revision 1.2Jan 31, 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

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Assembly

Deposited unit
A: Cholinesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,97823
Polymers59,7141
Non-polymers4,26422
Water4,432246
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6410 Å2
ΔGint11 kcal/mol
Surface area21330 Å2
Unit cell
Length a, b, c (Å)154.484, 154.484, 128.165
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) and 530STOP ...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) and 530STOP (recombinant devoir of the C-terminal part.
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 , 4 types, 7 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: 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
#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


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
#7: Sugar ChemComp-SIA / N-acetyl-alpha-neuraminic acid / N-acetylneuraminic acid / sialic acid / alpha-sialic acid / O-SIALIC ACID


Type: D-saccharide, alpha linking / Mass: 309.270 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H19NO9
IdentifierTypeProgram
DNeup5AcaCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-a-D-neuraminic acidCOMMON NAMEGMML 1.0
a-D-Neup5AcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
Neu5AcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 6 types, 261 molecules

#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Chemical ChemComp-S6Q / ~{N}-(phenylmethyl)-2-[1-(phenylsulfonyl)indol-4-yl]oxy-ethanamine


Mass: 406.497 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H22N2O3S / Feature type: SUBJECT OF INVESTIGATION
#8: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#9: 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
#10: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C3H8O3
#11: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 246 / 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: 3.2 Å3/Da / Density % sol: 61.58 %
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: 0.97625 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jul 13, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 2→48.85 Å / Num. obs: 52489 / % possible obs: 99.93 % / Redundancy: 8.3 % / Biso Wilson estimate: 36.08 Å2 / CC1/2: 1 / CC star: 1 / Rmerge(I) obs: 0.06085 / Rpim(I) all: 0.02226 / Rrim(I) all: 0.06492 / Net I/σ(I): 21.39
Reflection shellResolution: 2→2.071 Å / Redundancy: 8 % / Rmerge(I) obs: 0.8328 / Mean I/σ(I) obs: 2.49 / Num. unique obs: 5171 / CC1/2: 0.798 / CC star: 0.942 / Rpim(I) all: 0.3113 / Rrim(I) all: 0.8904 / % possible all: 100

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Processing

Software
NameVersionClassification
MxCuBEdata collection
XDSdata reduction
XSCALEdata scaling
PHASERphasing
PHENIX1.19rc4_4035refinement
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1p0i

1p0i


Resolution: 2→48.85 Å / SU ML: 0.1891 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 19.4548
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Details: modelisation of alternate position of a loop that moves upon ligand binding
RfactorNum. reflection% reflectionSelection details
Rfree0.1974 2524 4.81 %random
Rwork0.1728 49965 --
obs0.174 52489 99.95 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 43.63 Å2
Refinement stepCycle: LAST / Resolution: 2→48.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4195 0 275 246 4716
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00914640
X-RAY DIFFRACTIONf_angle_d1.03076300
X-RAY DIFFRACTIONf_chiral_restr0.0656692
X-RAY DIFFRACTIONf_plane_restr0.0079785
X-RAY DIFFRACTIONf_dihedral_angle_d10.7067688
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2-2.040.27381420.23612765X-RAY DIFFRACTION100
2.04-2.080.27861220.22352745X-RAY DIFFRACTION100
2.08-2.120.26831400.21062723X-RAY DIFFRACTION100
2.12-2.170.22241430.19512741X-RAY DIFFRACTION100
2.17-2.230.2271440.18922752X-RAY DIFFRACTION100
2.23-2.290.17851490.17362738X-RAY DIFFRACTION100
2.29-2.350.21921290.17062754X-RAY DIFFRACTION99.97
2.35-2.430.22831320.17292755X-RAY DIFFRACTION100
2.43-2.520.18911320.1822754X-RAY DIFFRACTION100
2.52-2.620.2121410.18282757X-RAY DIFFRACTION100
2.62-2.740.23281230.18392782X-RAY DIFFRACTION100
2.74-2.880.20051490.18432769X-RAY DIFFRACTION100
2.88-3.060.19551490.1812750X-RAY DIFFRACTION100
3.06-3.30.23131540.18362773X-RAY DIFFRACTION99.9
3.3-3.630.18951290.16692804X-RAY DIFFRACTION100
3.63-4.150.15311370.14922812X-RAY DIFFRACTION99.93
4.15-5.230.17781500.14082836X-RAY DIFFRACTION99.9
5.23-48.850.19261590.18662955X-RAY DIFFRACTION99.52
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)
11.26793306182-0.108056984870.3101617346071.587256563580.1208777420381.26060500086-0.02802555275810.254979937154-0.0507585367557-0.3624135047770.06114537133930.0888300618786-0.0681071159451-0.027669248792-0.03557471317450.347995172495-0.0350258126514-0.03875526191750.299253304507-0.03140266779120.257667794957134.312511068125.72664048626.3030116958
21.71345532927-0.3164322124280.008962416639873.080724523131.23365536882.36163296209-0.04916137476770.171628037865-0.448792636741-0.1383872613890.156346646708-0.2409255254040.3400538742870.382055343773-0.1261498621250.3034519121740.0158718577720.01082714444450.34083646388-0.05051904472680.382911273503149.885575204115.80775541433.5473937109
31.07935702347-0.08794423522090.6970137158322.43617808796-0.4437865814591.383631241440.0427044376529-0.242488055859-0.109317014510.1926717014910.04210039044250.1036247415220.0491025507974-0.146209501095-0.08711679936210.261370744879-0.00961611652724-0.002155329849440.327433236002-0.02228492000090.260206076955135.032827262122.53846300853.1340398918
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 4 through 209 )4 - 2091 - 206
22chain 'A' and (resid 210 through 316 )210 - 316207 - 313
33chain 'A' and (resid 317 through 529 )317 - 529314 - 526

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