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- PDB-9i5q: Recombinant human butyrylcholinesterase in complex with 2-(cycloh... -

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Basic information

Entry
Database: PDB / ID: 9i5q
TitleRecombinant human butyrylcholinesterase in complex with 2-(cyclohexylmethyl)-5-(2,4-difluorophenoxy)-N-(2-(3-(methoxymethyl)piperidin-1-yl)ethyl)-2H-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 / Aspirin ADME / Synthesis of PC / 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
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.36 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
Revision 1.1Sep 10, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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)63,38819
Polymers59,7141
Non-polymers3,67518
Water1,892105
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6440 Å2
ΔGint-35 kcal/mol
Surface area21240 Å2
Unit cell
Length a, b, c (Å)155.391, 155.391, 126.766
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 , 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-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

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Non-polymers , 6 types, 117 molecules

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


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-A1IZ3 / 5-[2,4-bis(fluoranyl)phenoxy]-2-(cyclohexylmethyl)-~{N}-[2-[(3~{R})-3-(methoxymethyl)piperidin-1-yl]ethyl]indazole-6-carboxamide / 2-(cyclohexylmethyl)-5-(2,4-difluorophenoxy)-N-(2-(3-(methoxymethyl)piperidin-1-yl)ethyl)-2H-indazole-6-carboxamide


Mass: 540.645 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H38F2N4O3 / Feature type: SUBJECT OF INVESTIGATION
#7: 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
#8: Chemical
ChemComp-SO4 / SULFATE ION


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


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 105 / 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: 61.61 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5 / 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: 0.8731 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jul 1, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8731 Å / Relative weight: 1
ReflectionResolution: 2.36→41.51 Å / Num. obs: 31344 / % possible obs: 97.92 % / Redundancy: 8.4 % / Biso Wilson estimate: 53.14 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.1105 / Rpim(I) all: 0.03898 / Rrim(I) all: 0.1176 / Net I/σ(I): 10.98
Reflection shellResolution: 2.36→2.44 Å / Rmerge(I) obs: 1.282 / Mean I/σ(I) obs: 1.18 / Num. unique obs: 2803 / CC1/2: 0.471 / Rpim(I) all: 0.4565 / Rrim(I) all: 1.366

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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: 2.36→41.51 Å / SU ML: 0.3192 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.3321
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.222 1577 5.04 %
Rwork0.1821 29728 -
obs0.1841 31305 97.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 62.84 Å2
Refinement stepCycle: LAST / Resolution: 2.36→41.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4203 0 234 105 4542
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00824584
X-RAY DIFFRACTIONf_angle_d0.99786229
X-RAY DIFFRACTIONf_chiral_restr0.0596685
X-RAY DIFFRACTIONf_plane_restr0.0057779
X-RAY DIFFRACTIONf_dihedral_angle_d17.89631829
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.36-2.440.34861320.31352639X-RAY DIFFRACTION96.82
2.44-2.530.33231560.28082668X-RAY DIFFRACTION99.16
2.53-2.630.32561490.26182675X-RAY DIFFRACTION98.88
2.63-2.750.32091300.25492713X-RAY DIFFRACTION98.72
2.75-2.890.28261400.23072702X-RAY DIFFRACTION98.44
2.89-3.070.25821590.20172650X-RAY DIFFRACTION97.91
3.07-3.310.22251440.19222686X-RAY DIFFRACTION98.43
3.31-3.640.21241490.17972715X-RAY DIFFRACTION98.18
3.64-4.170.24111310.14822716X-RAY DIFFRACTION97.94
4.17-5.250.15411310.13912758X-RAY DIFFRACTION97.27
5.25-41.510.18771560.17262806X-RAY DIFFRACTION95.64
Refinement TLS params.Method: refined / Origin x: -16.926386719 Å / Origin y: -31.9773143368 Å / Origin z: -25.0711578951 Å
111213212223313233
T0.436851943713 Å2-0.0206762902993 Å2-0.00349274453536 Å2-0.412409120355 Å2-0.0493073093909 Å2--0.454203307122 Å2
L0.429666620144 °20.141325917804 °20.246854739101 °2-0.619171908712 °20.00561477490809 °2--0.822611469529 °2
S-0.00457435854721 Å °-0.00773878837124 Å °-0.0883775407909 Å °-0.0494518266615 Å °0.0446202229388 Å °-0.00543747414063 Å °0.0620675808585 Å °-0.0388408072692 Å °1.4349405114E-5 Å °
Refinement TLS groupSelection details: chain 'A' and (resid 3 through 529 )

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