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- PDB-1eve: THREE DIMENSIONAL STRUCTURE OF THE ANTI-ALZHEIMER DRUG, E2020 (AR... -

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Entry
Database: PDB / ID: 1eve
TitleTHREE DIMENSIONAL STRUCTURE OF THE ANTI-ALZHEIMER DRUG, E2020 (ARICEPT), COMPLEXED WITH ITS TARGET ACETYLCHOLINESTERASE
ComponentsACETYLCHOLINESTERASE
KeywordsSERINE HYDROLASE / ALZHEIMER'S DISEASE / DRUG / ALPHA/BETA HYDROLASE / NEUROTRANSMITTER CLEAVAGE / CATALYTIC TRIAD / GLYCOSYLATED PROTEIN
Function / homology
Function and homology information


acetylcholine catabolic process in synaptic cleft / acetylcholinesterase / acetylcholinesterase activity / synaptic cleft / side of membrane / synapse / plasma membrane
Similarity search - Function
Acetylcholinesterase, fish/snake / 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, catalytic domain / Alpha/Beta hydrolase fold ...Acetylcholinesterase, fish/snake / 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, catalytic domain / Alpha/Beta hydrolase fold / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-E20 / Acetylcholinesterase
Similarity search - Component
Biological speciesTorpedo californica (Pacific electric ray)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsKryger, G. / Silman, I. / Sussman, J.L.
Citation
Journal: Structure Fold.Des. / Year: 1999
Title: Structure of acetylcholinesterase complexed with E2020 (Aricept): implications for the design of new anti-Alzheimer drugs.
Authors: Kryger, G. / Silman, I. / Sussman, J.L.
#1: Journal: Bioorg.Med.Chem. / Year: 1996
Title: The Rationale for E2020 as a Potent Acetylcholinesterase Inhibitor
Authors: Kawakami, Y. / Inoue, A. / Kawai, T. / Wakita, M. / Sugimoto, H. / Hopfinger, A.J.
#2: Journal: Science / Year: 1991
Title: Atomic Structure of Acetylcholinesterase from Torpedo Californica: A Prototypic Acetylcholine-Binding Protein
Authors: Sussman, J.L. / Harel, M. / Frolow, F. / Oefner, C. / Goldman, A. / Toker, L. / Silman, I.
History
DepositionMar 4, 1998Processing site: BNL
Revision 1.0Jan 20, 1999Provider: repository / Type: Initial release
Revision 1.1Mar 24, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Non-polymer description / Version format compliance
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_struct_special_symmetry / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_entity_id / _chem_comp.name / _chem_comp.type / _pdbx_entity_nonpoly.entity_id / _pdbx_entity_nonpoly.name / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_special_symmetry.label_asym_id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Aug 9, 2023Group: Database references / Refinement description / Structure summary
Category: chem_comp / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Remark 650HELIX THE ENZYME IS A GPI-ANCHORED DIMER, THE TWO MONOMERS IN THE DIMER ARE RELATED BY ...HELIX THE ENZYME IS A GPI-ANCHORED DIMER, THE TWO MONOMERS IN THE DIMER ARE RELATED BY CRYSTALLOGRAPHIC TWO-FOLD SYMMETRY AND GENERATE A FOUR HELIX BUNDLE A365-A375 AND A518-A535.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: ACETYLCHOLINESTERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,7936
Polymers61,3251
Non-polymers1,4685
Water7,134396
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)111.925, 111.925, 136.896
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number152
Space group name H-MP3121
Components on special symmetry positions
IDModelComponents
11A-1381-

HOH

21A-1382-

HOH

DetailsTORPEDO CALIFORNICA ACETYLCHOLINESTERASE IS A G2 DIMER IN SOLUTION (SEE SUSSMAN 1988). THE ASYMMETRIC UNIT CONTAINS A MONOMER, WITH THE CRYSTALLOGRAPHIC TWO-FOLD AXIS RELATING THE TWO MONOMERS IN A DIMER. THIS STRUCTURE IS MORE COMPLETE THAN THE STARTING MODEL OF THE NATIVE STRUCTURE (PDB ID 2ACE). RESIDUES THAT ARE NOT SEEN IN THE CRYSTAL STRUCTURE DUE TO DISORDER INCLUDE THE N-TERMINAL RESIDUE ASP 1 AND THE C-TERMINAL RESIDUES AFTER THR 535. THR 535 IS THE LAST RESIDUE OBSERVED AT THE C-TERMINUS. THE LIGAND SEEN IN THE STRUCTURE, E2020 (DONEPEZIL, ARICEPT), IS A POTENT REVERSIBLE ACHE INHIBITOR WHICH IS AN FDA APPROVED DRUG FOR THE SYMPTOMATIC TREATMENT OF ALZHEIMER'S DISEASE (SEE KAWAKAMI 1996). THE CHIRAL INHIBITOR WAS SOAKED AS A RACEMATE BUT ONLY THE R FORM SEEMS TO BIND TO THE ENZYME ACCORDING TO THE X-RAY DIFFRACTION EXPERIMENT.

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Components

#1: Protein ACETYLCHOLINESTERASE /


Mass: 61325.090 Da / Num. of mol.: 1 / Source method: isolated from a natural source
Source: (natural) Torpedo californica (Pacific electric ray)
Organ: ELECTRIC ORGAN / Variant: G2 FORM / Tissue: ELECTROPLAQUE / References: UniProt: P04058, acetylcholinesterase
#2: 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
#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 / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 3
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: Chemical ChemComp-E20 / 1-BENZYL-4-[(5,6-DIMETHOXY-1-INDANON-2-YL)METHYL]PIPERIDINE / E2020 / Edgenuity


Mass: 379.492 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H29NO3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 396 / Source method: isolated from a natural source / Formula: H2O

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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: 3.8 Å3/Da / Density % sol: 68 %
Crystal growpH: 5.8 / Details: pH 5.8
Crystal grow
*PLUS
Temperature: 4 ℃ / Method: vapor diffusion, hanging drop
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-ID
112 mg/mlprotein1drop
238 %PEG2001reservoir
30.1 M2-N-morpholino-ethane-sulfonate1reservoir

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5418
DetectorType: RIGAKU / Detector: IMAGE PLATE / Date: May 1, 1997 / Details: MIRRORS
RadiationMonochromator: NI FILTER / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.5→30 Å / Num. obs: 34266 / % possible obs: 98.1 % / Observed criterion σ(I): 0 / Biso Wilson estimate: 39.1 Å2 / Rsym value: 0.05
Reflection shellResolution: 2.5→2.59 Å / Mean I/σ(I) obs: 2.8 / Rsym value: 0.252 / % possible all: 95
Reflection
*PLUS
Rmerge(I) obs: 0.05
Reflection shell
*PLUS
% possible obs: 95 % / Rmerge(I) obs: 0.252

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Processing

Software
NameVersionClassification
DENZOdata reduction
SCALEPACKdata scaling
X-PLOR3.851model building
X-PLOR3.851refinement
X-PLOR3.851phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2ACE

2ace


Resolution: 2.5→30 Å / Rfactor Rfree error: 0.005 / Data cutoff high absF: 10000000 / Data cutoff low absF: 0.001 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Details: BULK SOLVENT MODEL USED
RfactorNum. reflection% reflectionSelection details
Rfree0.228 1976 5.8 %RANDOM
Rwork0.188 ---
obs0.188 34240 98.3 %-
Displacement parametersBiso mean: 29.3 Å2
Baniso -1Baniso -2Baniso -3
1-1.06 Å2-0.48 Å20 Å2
2--1.06 Å20 Å2
3----2.13 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.3 Å0.25 Å
Luzzati d res low-30 Å
Luzzati sigma a0.39 Å0.3 Å
Refinement stepCycle: LAST / Resolution: 2.5→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4254 0 98 396 4748
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONx_bond_d0.005
X-RAY DIFFRACTIONx_bond_d_na
X-RAY DIFFRACTIONx_bond_d_prot
X-RAY DIFFRACTIONx_angle_d
X-RAY DIFFRACTIONx_angle_d_na
X-RAY DIFFRACTIONx_angle_d_prot
X-RAY DIFFRACTIONx_angle_deg1.2
X-RAY DIFFRACTIONx_angle_deg_na
X-RAY DIFFRACTIONx_angle_deg_prot
X-RAY DIFFRACTIONx_dihedral_angle_d23.1
X-RAY DIFFRACTIONx_dihedral_angle_d_na
X-RAY DIFFRACTIONx_dihedral_angle_d_prot
X-RAY DIFFRACTIONx_improper_angle_d0.97
X-RAY DIFFRACTIONx_improper_angle_d_na
X-RAY DIFFRACTIONx_improper_angle_d_prot
X-RAY DIFFRACTIONx_mcbond_it3.11.5
X-RAY DIFFRACTIONx_mcangle_it4.592
X-RAY DIFFRACTIONx_scbond_it5.132
X-RAY DIFFRACTIONx_scangle_it6.882.5
LS refinement shellResolution: 2.5→2.66 Å / Rfactor Rfree error: 0.021 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.367 295 5.3 %
Rwork0.286 5288 -
obs--97.7 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PARHCSDX.PROTOPHCSDX.PRO
X-RAY DIFFRACTION2PARAM19.SOLTOPH11.WAT
X-RAY DIFFRACTION3CBH3.PARAME2020.TOP
X-RAY DIFFRACTION4LEARN.E2020CBH3-P.CHO
Refinement
*PLUS
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_dihedral_angle_d
X-RAY DIFFRACTIONx_dihedral_angle_deg23.1
X-RAY DIFFRACTIONx_improper_angle_d
X-RAY DIFFRACTIONx_improper_angle_deg0.97
LS refinement shell
*PLUS
Rfactor obs: 0.286

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