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- PDB-7bo3: Human Butyrylcholinesterase in complex with N-(2-(1H-Indol-3-yl)e... -

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Basic information

Entry
Database: PDB / ID: 7bo3
TitleHuman Butyrylcholinesterase in complex with N-(2-(1H-Indol-3-yl)ethyl)-2-cycloheptyl-N-methylethan-1-amine
ComponentsCholinesterase
KeywordsHYDROLASE / Butyrylcholinesterase / Complex / Inhibitor
Function / homology
Function and homology information


cholinesterase / cocaine metabolic process / neuroblast differentiation / Neurotransmitter clearance / choline metabolic process / 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 / choline metabolic process / choline binding / response to folic acid / response to alkaloid / 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 / 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
Similarity search - Domain/homology
Chem-IA4 / N-acetyl-alpha-neuraminic acid / Cholinesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsBrazzolotto, X. / Meden, A. / Knez, D. / Nachon, F. / Gobec, S.
Funding support France, 1items
OrganizationGrant numberCountry
French Ministry of Armed ForcesNBC-5-C-4210 France
CitationJournal: Eur.J.Med.Chem. / Year: 2022
Title: From tryptophan-based amides to tertiary amines: Optimization of a butyrylcholinesterase inhibitor series.
Authors: Meden, A. / Knez, D. / Brazzolotto, X. / Nachon, F. / Dias, J. / Svete, J. / Stojan, J. / Groselj, U. / Gobec, S.
History
DepositionJan 23, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 2, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 16, 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.page_first / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Mar 30, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_last ..._citation.journal_volume / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Jan 31, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,05416
Polymers59,7141
Non-polymers3,34015
Water2,126118
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4430 Å2
ΔGint-7 kcal/mol
Surface area21430 Å2
Unit cell
Length a, b, c (Å)154.510, 154.510, 127.600
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)
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.: 2
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.: 1
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 / 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
#9: Sugar ChemComp-SIA / N-acetyl-alpha-neuraminic acid / N-acetylneuraminic acid / sialic acid / alpha-sialic acid / O-SIALIC ACID / 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 , 5 types, 126 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-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#7: 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
#8: Chemical ChemComp-IA4 / ~{N}-(2-cycloheptylethyl)-2-(1~{H}-indol-3-yl)-~{N}-methyl-ethanamine


Mass: 298.466 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H30N2 / Feature type: SUBJECT OF INVESTIGATION
#10: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 118 / 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: 3.19 Å3/Da / Density % sol: 61.42 %
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 2 / Wavelength: 0.97888 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Mar 14, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97888 Å / Relative weight: 1
ReflectionResolution: 2.2→41.5 Å / Num. obs: 39314 / % possible obs: 99.91 % / Redundancy: 26.3 % / Biso Wilson estimate: 48.91 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.1206 / Rpim(I) all: 0.02393 / Rrim(I) all: 0.123 / Net I/σ(I): 23.81
Reflection shellResolution: 2.2→2.279 Å / Redundancy: 22.9 % / Rmerge(I) obs: 2.151 / Mean I/σ(I) obs: 1.34 / Num. unique obs: 3865 / CC1/2: 0.69 / Rpim(I) all: 0.4574 / Rrim(I) all: 2.2 / % possible all: 99.79

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Processing

Software
NameVersionClassification
MxCuBE1.19rc4_4035data collection
XDSdata reduction
XSCALEdata scaling
PHASERphasing
PHENIX1.19rc4_4035refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1p0i

1p0i


Resolution: 2.2→41.5 Å / SU ML: 0.2812 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 25.6436
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflectionSelection details
Rfree0.217 1179 3 %Random
Rwork0.1834 38112 --
obs0.1844 39291 99.93 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 58.55 Å2
Refinement stepCycle: LAST / Resolution: 2.2→41.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4191 0 215 118 4524
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00824565
X-RAY DIFFRACTIONf_angle_d0.89876208
X-RAY DIFFRACTIONf_chiral_restr0.0558685
X-RAY DIFFRACTIONf_plane_restr0.0077778
X-RAY DIFFRACTIONf_dihedral_angle_d8.7248661
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.30.34211450.28884706X-RAY DIFFRACTION99.84
2.3-2.420.27341450.23554685X-RAY DIFFRACTION99.92
2.42-2.570.27021460.21624710X-RAY DIFFRACTION100
2.57-2.770.29511460.21674718X-RAY DIFFRACTION100
2.77-3.050.22861460.19514730X-RAY DIFFRACTION99.98
3.05-3.490.24241470.18824762X-RAY DIFFRACTION99.9
3.49-4.40.17691490.1594810X-RAY DIFFRACTION100
4.4-41.50.1931550.16854991X-RAY DIFFRACTION99.86
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)
11.683878556460.0754007086755-0.2041967946991.65527020358-0.1261376914981.79870343672-0.08034235282750.2919427265430.0339452944606-0.4137176858920.0928518414152-0.06756475105910.09830467261170.0744380211111-0.005604826798510.49876432758-0.03795975114240.03831603213660.4178336201920.04343246980190.38510476262820.179176794428.788356249926.0691130315
21.29991759105-0.08609141575760.08194318704551.37428193172-0.7553160287612.51793166819-0.08597024716820.1879049200940.407869097848-0.09662778064940.1712174450140.258221256837-0.430155429436-0.344616725724-0.09108464146530.4496211488160.00694370444294-0.03382752988270.4491790932970.07586120846430.5421277353184.3393796923538.223372235633.1041963753
31.2723852421-0.102749015658-0.6992536468522.922461460780.4295298538921.748795514120.0239671070611-0.2984430354990.1028188304760.2096091758310.05020492956330.00168380308042-0.04300941924390.179356924976-0.07292709553780.359436451654-0.0179652922505-0.003909591941730.4398485387530.04319471486490.3563702840619.417786891632.034301512252.8737613771
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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