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- PDB-9i5p: Recombinant human butyrylcholinesterase in complex with 1-(isobut... -

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Basic information

Entry
Database: PDB / ID: 9i5p
TitleRecombinant human butyrylcholinesterase in complex with 1-(isobutylmethyl)-5-(2,4-difluorobenzyl)-N-(2-(dimethylamino)ethyl)-1H-indazole-6-carboxamide
ComponentsCholinesterase
KeywordsHYDROLASE / Butyrylcholinesterase / inhibitor / complex
Function / homology
Function and homology information


cholinesterase / : / neuroblast differentiation / response to folic acid / choline binding / Neurotransmitter clearance / cholinesterase activity / response to alkaloid / choline metabolic process / acetylcholine catabolic process ...cholinesterase / : / neuroblast differentiation / response to folic acid / choline binding / Neurotransmitter clearance / cholinesterase activity / response to alkaloid / choline metabolic process / acetylcholine catabolic process / negative regulation of synaptic transmission / hydrolase activity, acting on ester bonds / peptide hormone processing / acetylcholinesterase activity / nuclear envelope lumen / Synthesis of PC / Aspirin ADME / 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
: / N-acetyl-alpha-neuraminic acid / Cholinesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.75 Å
AuthorsBrazzolotto, X. / Ferjancic Benetik, S. / Knez, D. / Proj, M. / 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: Targeting Neuroinflammation and Cognitive Decline: First-in-Class Dual Butyrylcholinesterase and p38 alpha Mitogen-Activated Protein Kinase Inhibitors.
Authors: Ferjancic Benetik, S. / Proj, M. / Knez, D. / Kosak, U. / Meden, A. / Krajsek, K. / Pislar, A. / Horvat, S. / Svajger, U. / Tesic, N. / Pulkrabkova, L. / Soukup, O. / Skarka, A. / Andrys, R. ...Authors: Ferjancic Benetik, S. / Proj, M. / Knez, D. / Kosak, U. / Meden, A. / Krajsek, K. / Pislar, A. / Horvat, S. / Svajger, U. / Tesic, N. / Pulkrabkova, L. / Soukup, O. / Skarka, A. / Andrys, R. / Brazzolotto, X. / Igert, A. / Nachon, F. / Dias, J. / Detka, J. / Gdula-Argasinska, J. / Wyska, E. / Szafarz, M. / Manik, A. / Plachtij, N. / Musilek, K. / Salat, K. / Obreza, A. / Gobec, S.
History
DepositionJan 28, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 20, 2025Provider: repository / Type: Initial release

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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)63,49314
Polymers59,7141
Non-polymers3,78013
Water1,26170
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4550 Å2
ΔGint14 kcal/mol
Surface area22080 Å2
Unit cell
Length a, b, c (Å)154.080, 154.080, 127.253
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
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 , 5 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.: 3
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 beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 732.682 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4[LFucpa1-6]DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1221m-1a_1-5]/1-1-2-3/a4-b1_a6-d1_b4-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}[(6+1)][a-L-Fucp]{}}}LINUCSPDB-CARE
#4: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}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


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / 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 , 5 types, 76 molecules

#6: Chemical ChemComp-A1A2O / 5-[(2,4-difluorophenyl)methyl]-N-[2-(dimethylamino)ethyl]-1-(2-methylpropyl)-1H-indazole-6-carboxamide


Mass: 414.491 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H28F2N4O / Feature type: SUBJECT OF INVESTIGATION
#8: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#11: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 70 / 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: 3.16 Å3/Da / Density % sol: 61.1 %
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: MASSIF-3 / Wavelength: 0.9677 Å
DetectorType: DECTRIS EIGER X 4M / Detector: PIXEL / Date: Feb 12, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9677 Å / Relative weight: 1
ReflectionResolution: 2.75→47.63 Å / Num. obs: 20122 / % possible obs: 99.54 % / Redundancy: 9.1 % / Biso Wilson estimate: 60.39 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.1721 / Rpim(I) all: 0.0596 / Rrim(I) all: 0.1825 / Net I/σ(I): 9.23
Reflection shellResolution: 2.75→2.9 Å / Rmerge(I) obs: 1.422 / Mean I/σ(I) obs: 1.47 / Num. unique obs: 2848 / CC1/2: 0.585 / Rpim(I) all: 0.4869 / Rrim(I) all: 1.506

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Processing

Software
NameVersionClassification
MxCuBEdata collection
XDSdata reduction
XSCALEdata scaling
PHASERphasing
Cootmodel building
PHENIX1.21.2_5419refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.75→47.63 Å / SU ML: 0.4424 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 26.2367
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2288 1034 5.14 %
Rwork0.1852 19083 -
obs0.1874 20117 99.54 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 68.48 Å2
Refinement stepCycle: LAST / Resolution: 2.75→47.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4195 0 247 70 4512
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00834609
X-RAY DIFFRACTIONf_angle_d1.01956273
X-RAY DIFFRACTIONf_chiral_restr0.055700
X-RAY DIFFRACTIONf_plane_restr0.0067783
X-RAY DIFFRACTIONf_dihedral_angle_d19.15151898
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.75-2.90.42891360.31052711X-RAY DIFFRACTION99.96
2.9-3.080.29391470.2552690X-RAY DIFFRACTION100
3.08-3.310.27341490.21512682X-RAY DIFFRACTION100
3.31-3.650.21561570.18952702X-RAY DIFFRACTION99.86
3.65-4.170.21241420.14782695X-RAY DIFFRACTION98.88
4.18-5.260.19461500.15032729X-RAY DIFFRACTION98.63
5.26-47.630.21071530.18132874X-RAY DIFFRACTION99.54
Refinement TLS params.Method: refined / Origin x: -16.6532336623 Å / Origin y: -31.9625974704 Å / Origin z: -24.8977053804 Å
111213212223313233
T0.445314921939 Å2-0.0211531050837 Å2-0.0255463782568 Å2-0.435178654309 Å2-0.0378070822794 Å2--0.497808457273 Å2
L1.13481483115 °20.214744336075 °20.306530852229 °2-1.19354528887 °20.10442904012 °2--1.39904017033 °2
S-0.00256285070246 Å °-0.0280802368413 Å °-0.147391935419 Å °-0.100379557735 Å °0.0550223181067 Å °-0.0676557816073 Å °0.0435080525076 Å °-0.0335948114073 Å °-0.0441974532104 Å °
Refinement TLS groupSelection details: chain 'A' and (resid 4 through 529 )

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