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

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Basic information

Entry
Database: PDB / ID: 7awh
TitleCrystal structure of human butyrylcholinesterase in complex with tert-butyl 3-(((2-((1-(benzenesulfonyl)-1H-indol-4-yl)oxy)ethyl)amino)methyl)piperidine-1-carboxylate
ComponentsCholinesterase
KeywordsHYDROLASE / butyrylcholinesterase / inhibitor complex
Function / homology
Function and homology information


cholinesterase / cocaine metabolic process / neuroblast differentiation / Neurotransmitter clearance / cholinesterase activity / 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 / cholinesterase activity / choline binding / response to folic acid / response to alkaloid / acetylcholine catabolic process / negative regulation of synaptic transmission / peptide hormone processing / acetylcholinesterase activity / choline metabolic process / hydrolase activity, acting on ester bonds / Aspirin ADME / nuclear envelope lumen / 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-S8K / Cholinesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsBrazzolotto, X. / Wichur, T. / Wieckowska, A.
Funding support France, 1items
OrganizationGrant numberCountry
French Ministry of Armed ForcesNBC-5-C-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

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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)63,27817
Polymers59,7141
Non-polymers3,56416
Water1,76598
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4830 Å2
ΔGint-6 kcal/mol
Surface area21440 Å2
Unit cell
Length a, b, c (Å)154.470, 154.470, 127.420
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-798-

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) 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 , 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 / 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

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Non-polymers , 6 types, 108 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.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#8: Chemical ChemComp-S8K / ~{tert}-butyl (3~{S})-3-[[2-[1-(phenylsulfonyl)indol-4-yl]oxyethylamino]methyl]piperidine-1-carboxylate


Mass: 513.649 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H35N3O5S / Feature type: SUBJECT OF INVESTIGATION
#9: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#10: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 98 / 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: 3.18 Å3/Da / Density % sol: 61.35 %
Crystal growTemperature: 295 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 1 / Wavelength: 0.978564918041 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 4, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.978564918041 Å / Relative weight: 1
ReflectionResolution: 2.3→48.85 Å / Num. obs: 34407 / % possible obs: 99.92 % / Redundancy: 26.7 % / Biso Wilson estimate: 60.77 Å2 / CC1/2: 0.999 / CC star: 1 / Rmerge(I) obs: 0.1269 / Rpim(I) all: 0.02534 / Rrim(I) all: 0.1294 / Net I/σ(I): 19.16
Reflection shellResolution: 2.3→2.382 Å / Redundancy: 27.9 % / Rmerge(I) obs: 2.503 / Mean I/σ(I) obs: 1.42 / Num. unique obs: 3385 / CC1/2: 0.615 / CC star: 0.873 / Rpim(I) all: 0.4799 / Rrim(I) all: 2.549 / % possible all: 99.97

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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: 2.3→48.85 Å / SU ML: 0.3419 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 27.2955
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflectionSelection details
Rfree0.2218 1032 3 %random
Rwork0.1919 33357 --
obs0.1928 34389 99.94 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 68.99 Å2
Refinement stepCycle: LAST / Resolution: 2.3→48.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4195 0 229 98 4522
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00864615
X-RAY DIFFRACTIONf_angle_d0.96646278
X-RAY DIFFRACTIONf_chiral_restr0.0548689
X-RAY DIFFRACTIONf_plane_restr0.0075786
X-RAY DIFFRACTIONf_dihedral_angle_d13.8603687
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.420.38911450.33414688X-RAY DIFFRACTION99.96
2.42-2.570.30771450.29724700X-RAY DIFFRACTION100
2.57-2.770.31551460.25194709X-RAY DIFFRACTION100
2.77-3.050.25621460.21784719X-RAY DIFFRACTION100
3.05-3.490.231470.19924761X-RAY DIFFRACTION99.88
3.49-4.40.18861480.16444796X-RAY DIFFRACTION99.9
4.4-48.850.19611550.17054984X-RAY DIFFRACTION99.88
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)
10.2278429725120.244364687076-0.2700594497710.482455833881-0.1454293029841.00955691567-0.04256252051170.06688138650130.0798900837822-0.1717061207850.0960928377003-0.03305578492820.02868810383640.03151837778661.72992102774E-50.599759343004-0.02076187122620.02437609224360.5541020147160.03652751499330.5558196101918.895614790828.456474438727.3522785198
20.243160584642-0.0985387505328-0.07441407548810.009290847272630.06951681154510.41413455086-0.08205208317350.04667511091360.141209401587-0.02674417842560.1124691038790.0910235658-0.101153114281-0.1862676925823.10576625276E-50.6302634164590.00859589005149-0.07184932980030.5947739400410.07842668227190.7090269195793.4166359433842.285239475231.8505845957
30.292327179203-0.0813013061752-0.4438370379380.6717336996220.1581897272850.9349835927950.0282388240383-0.1807728792260.03885445987270.05906984670250.0379473473388-9.46799937711E-5-0.05456641360560.0938934619796.01868857976E-50.514444683572-0.01518281644310.0141198584240.5629624285750.02478184352440.56416441387519.43030643231.87332263952.8111301622
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 235 )4 - 2351 - 232
22chain 'A' and (resid 236 through 316 )236 - 316233 - 313
33chain 'A' and (resid 317 through 529 )317 - 529314 - 526

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