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- PDB-9i02: Structure of recombinant human butyrylcholinesterase in complex w... -

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Basic information

Entry
Database: PDB / ID: 9i02
TitleStructure of recombinant human butyrylcholinesterase in complex with (S)-N-((1-benzylpyrrolidin-3-yl)methyl)-N-methylnaphthalene-2-sulfonamide
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
: / PROPANOIC ACID / N-acetyl-alpha-neuraminic acid / Cholinesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.58 Å
AuthorsBrazzolotto, X. / Kosak, U. / Gobec, S. / Nachon, F.
Funding support France, 1items
OrganizationGrant numberCountry
French Ministry of Armed ForcesNBC-5-C-2316 France
CitationJournal: J.Med.Chem. / Year: 2025
Title: Lead Optimization of a Butyrylcholinesterase Inhibitor for the Treatment of Alzheimer's Disease.
Authors: Kosak, U. / Strasek Benedik, N. / Knez, D. / Zakelj, S. / Trontelj, J. / Pislar, A. / Horvat, S. / Bolje, A. / Znidarsic, N. / Grgurevic, N. / Svara, T. / Kljun, J. / Skrzypczak-Wiercioch, A. ...Authors: Kosak, U. / Strasek Benedik, N. / Knez, D. / Zakelj, S. / Trontelj, J. / Pislar, A. / Horvat, S. / Bolje, A. / Znidarsic, N. / Grgurevic, N. / Svara, T. / Kljun, J. / Skrzypczak-Wiercioch, A. / Lv, B. / Xiong, Y. / Wang, Q. / Bian, R. / Shao, J. / Dias, J. / Nachon, F. / Brazzolotto, X. / Stojan, J. / Sun, H. / Salat, K. / Gobec, S.
History
DepositionJan 14, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 2, 2025Provider: repository / Type: Initial release

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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)64,12422
Polymers59,7141
Non-polymers4,41021
Water1,78399
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)154.670, 154.670, 127.340
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-799-

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
Details: 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: (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 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-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
#3: 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
#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.: 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
#9: 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 , 7 types, 113 molecules

#5: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C3H8O3
#6: 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
#7: Chemical ChemComp-A1IYP / ~{N}-methyl-~{N}-[[(3~{S})-1-(phenylmethyl)pyrrolidin-3-yl]methyl]naphthalene-2-sulfonamide


Mass: 394.530 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H26N2O2S / Feature type: SUBJECT OF INVESTIGATION
#8: Chemical ChemComp-PPI / PROPANOIC ACID


Mass: 74.079 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H6O2
#10: Chemical
ChemComp-SO4 / SULFATE ION


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


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#12: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 99 / 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: 3.19 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: ESRF / Beamline: BM07 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 3, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.58→49.15 Å / Num. obs: 23919 / % possible obs: 97.21 % / Redundancy: 7.4 % / Biso Wilson estimate: 57.15 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.1405 / Rpim(I) all: 0.0536 / Rrim(I) all: 0.151 / Net I/σ(I): 10.21
Reflection shellResolution: 2.58→2.672 Å / Redundancy: 7.4 % / Num. unique obs: 2276 / CC1/2: 0.469 / % possible all: 94.28

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Processing

Software
NameVersionClassification
MxCuBEdata collection
XDSdata reduction
XSCALEdata scaling
Cootmodel building
PHASERphasing
PHENIX1.20.1_4487refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.58→49.15 Å / SU ML: 0.3551 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 24.6531
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2393 1197 5.01 %
Rwork0.1795 22716 -
obs0.1825 23913 96.76 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 64.41 Å2
Refinement stepCycle: LAST / Resolution: 2.58→49.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4203 0 284 99 4586
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00934641
X-RAY DIFFRACTIONf_angle_d1.03076308
X-RAY DIFFRACTIONf_chiral_restr0.0575700
X-RAY DIFFRACTIONf_plane_restr0.007785
X-RAY DIFFRACTIONf_dihedral_angle_d10.0867695
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.58-2.680.321220.2822306X-RAY DIFFRACTION90.23
2.68-2.80.33471330.26532534X-RAY DIFFRACTION98.89
2.8-2.950.2721330.23962534X-RAY DIFFRACTION97.94
2.95-3.130.29561330.22352530X-RAY DIFFRACTION98.7
3.13-3.370.32491340.20782542X-RAY DIFFRACTION98.31
3.37-3.710.26971340.17562542X-RAY DIFFRACTION97.63
3.71-4.250.20221340.15092552X-RAY DIFFRACTION97.74
4.25-5.350.18651350.13842552X-RAY DIFFRACTION96.76
5.35-49.150.21511390.16932624X-RAY DIFFRACTION94.69
Refinement TLS params.Method: refined / Origin x: 16.937928045 Å / Origin y: 32.3785354805 Å / Origin z: 38.4159678532 Å
111213212223313233
T0.385894711435 Å2-0.0362723913118 Å20.00755820247538 Å2-0.364510795217 Å20.0453953468604 Å2--0.418176443988 Å2
L1.40561944563 °20.0686807939118 °2-0.26841881792 °2-1.4730069873 °2-0.0835163189747 °2--1.9876948443 °2
S0.00159689777214 Å °-0.00237194307513 Å °0.104263259977 Å °-0.13809206134 Å °0.0566987306424 Å °0.0396622950051 Å °-0.126301394486 Å °0.0824720717694 Å °-0.0510179505818 Å °
Refinement TLS groupSelection details: chain 'A'

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