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- PDB-6tt0: Crystal structure of a potent and reversible dual binding site Ac... -

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Basic information

Entry
Database: PDB / ID: 6tt0
TitleCrystal structure of a potent and reversible dual binding site Acetylcholinesterase chiral inhibitor
ComponentsAcetylcholinesterase
KeywordsHYDROLASE / dual binding site inhibitor / chiral separation / acetylcholinesterase / Alzheimer's disease
Function / homology
Function and homology information


acetylcholine catabolic process in synaptic cleft / choline metabolic process / acetylcholinesterase / acetylcholinesterase activity / synaptic cleft / side of membrane / synapse / extracellular space / plasma membrane
Similarity search - Function
Acetylcholinesterase, fish/snake / : / 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, catalytic domain ...Acetylcholinesterase, fish/snake / : / 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, catalytic domain / Alpha/Beta hydrolase fold / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-N9T / Acetylcholinesterase
Similarity search - Component
Biological speciesTetronarce californica (Pacific electric ray)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.80003021833 Å
Authorsde la Mora, E. / Mangiatordi, G.F. / Belviso, B.D. / Caliandro, R. / Colletier, J.P. / Catto, M.
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: Chiral Separation, X-ray Structure, and Biological Evaluation of a Potent and Reversible Dual Binding Site AChE Inhibitor.
Authors: Catto, M. / Pisani, L. / de la Mora, E. / Belviso, B.D. / Mangiatordi, G.F. / Pinto, A. / Palma, A. / Denora, N. / Caliandro, R. / Colletier, J.P. / Silman, I. / Nicolotti, O. / Altomare, C.D.
History
DepositionDec 22, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 10, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _entity.pdbx_description ..._chem_comp.name / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_conn.pdbx_role
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.2May 12, 2021Group: Derived calculations / Structure summary
Category: chem_comp / pdbx_struct_assembly ...chem_comp / pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / pdbx_struct_oper_list
Item: _chem_comp.pdbx_synonyms / _pdbx_struct_assembly.details ..._chem_comp.pdbx_synonyms / _pdbx_struct_assembly.details / _pdbx_struct_assembly.method_details / _pdbx_struct_assembly.oligomeric_count / _pdbx_struct_assembly.oligomeric_details
Revision 1.3Oct 4, 2023Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.4Jan 24, 2024Group: Refinement description / Category: pdbx_initial_refinement_model
Revision 1.5Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Acetylcholinesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,1954
Polymers65,3161
Non-polymers8793
Water1,58588
1
A: Acetylcholinesterase
hetero molecules

A: Acetylcholinesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)132,3898
Polymers130,6312
Non-polymers1,7586
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation6_559-x,-x+y,-z+13/31
Unit cell
Length a, b, c (Å)111.420, 111.420, 137.370
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121
Space group name HallP312"
Symmetry operation#1: x,y,z
#2: -y,x-y,z+1/3
#3: -x+y,-x,z+2/3
#4: x-y,-y,-z+2/3
#5: -x,-x+y,-z+1/3
#6: y,x,-z

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Components

#1: Protein Acetylcholinesterase / AChE


Mass: 65315.594 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: T. californica acetylcholinesterase
Source: (gene. exp.) Tetronarce californica (Pacific electric ray)
Gene: ache
Production host: Tetronarce californica (Pacific electric ray)
References: UniProt: P04058, acetylcholinesterase
#2: Chemical ChemComp-N9T / (1~{R},3~{S})-~{N}-(6,7-dimethoxy-2-oxidanylidene-chromen-3-yl)-3-[(phenylmethyl)amino]cyclohexane-1-carboxamide


Mass: 436.500 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H28N2O5 / Feature type: SUBJECT OF INVESTIGATION
#3: 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: isolated from a genetically manipulated source
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
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 88 / Source method: isolated from a natural source / Formula: H2O
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: 4.1 Å3/Da / Density % sol: 70 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: 32% PEG 200 100 mM MES pH 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 1.074 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 28, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.074 Å / Relative weight: 1
ReflectionResolution: 2.8→39.48 Å / Num. obs: 24409 / % possible obs: 98.1 % / Observed criterion σ(I): 1.5 / Redundancy: 1.8 % / Biso Wilson estimate: 67.6781327552 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.04067 / Rpim(I) all: 0.04067 / Rrim(I) all: 0.05751 / Net I/σ(I): 10.5
Reflection shellResolution: 2.8→2.9 Å / Redundancy: 1.8 % / Rmerge(I) obs: 0.3768 / Mean I/σ(I) obs: 1.57 / Num. unique obs: 4385 / CC1/2: 0.872 / Rsym value: 0.5328 / % possible all: 98.81

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Processing

Software
NameVersionClassification
PHENIX1.11.1_2575refinement
PHENIX1.11.1_2575refinement
XDSdata reduction
XSCALEdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2vt7

2vt7


Resolution: 2.80003021833→39.4797998252 Å / SU ML: 0.395506018796 / Cross valid method: FREE R-VALUE / σ(F): 1.34889918222 / Phase error: 27.3771183945
RfactorNum. reflection% reflection
Rfree0.235273529519 1189 4.88877924427 %
Rwork0.188337050801 --
obs0.190702741239 24321 98.1160238825 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 69.9462107358 Å2
Refinement stepCycle: LAST / Resolution: 2.80003021833→39.4797998252 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4244 0 60 88 4392
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.03137260646794435
X-RAY DIFFRACTIONf_angle_d1.362777819836027
X-RAY DIFFRACTIONf_chiral_restr0.0701859922473632
X-RAY DIFFRACTIONf_plane_restr0.00704724221652781
X-RAY DIFFRACTIONf_dihedral_angle_d18.64893047471614
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.80003021833-2.92740.3563676485591520.3208461413522870X-RAY DIFFRACTION98.7259065665
2.9274-3.08170.3271789653081450.2813623074872857X-RAY DIFFRACTION98.9452867502
3.0817-3.27470.3199783881111450.2406590082962891X-RAY DIFFRACTION98.6034426762
3.2747-3.52740.2556466704531380.2163736716882867X-RAY DIFFRACTION98.4277759581
3.5274-3.88210.2153100877411320.1737199370242903X-RAY DIFFRACTION98.7955729167
3.8821-4.44320.2341943578391420.1630888952322912X-RAY DIFFRACTION98.3891752577
4.4432-5.59540.2024712127831630.1534020085352890X-RAY DIFFRACTION97.8212111503
5.5954-39.47979982520.2133843605631720.1771441982972942X-RAY DIFFRACTION95.4044117647

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