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- PDB-1ut6: Structure of acetylcholinesterase (E.C. 3.1.1.7) complexed with N... -

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Entry
Database: PDB / ID: 1ut6
TitleStructure of acetylcholinesterase (E.C. 3.1.1.7) complexed with N-9-(1',2',3',4'-Tetrahydroacridinyl)-1,8- diaminooctane at 2.4 angstroms resolution.
ComponentsACETYLCHOLINESTERASE
KeywordsHYDROLASE / SERINE HYDROLASE / ACETYLCHOLINESTERASE / NEUROTRANSMITTER CLEAVAGE / ALZHEIMER'S DISEASE / BIVALENT LIGAND / DUAL-SITE BINDING / INHIBITOR / TACRINE / AMINE / HETERODIMER / SERINE ESTERASE SYNAPSE / MEMBRANE / NERVE / MUSCLE / GPI-ANCHOR NEUROTRANSMITTER DEGRADATION / GLYCOPROTEIN
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-A8N / Acetylcholinesterase
Similarity search - Component
Biological speciesTORPEDO CALIFORNICA (Pacific electric ray)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsBrumshtein, B. / Wong, D.M. / Greenblatt, H.M. / Carlier, P.R. / Pang, Y.-P. / Silman, I. / Sussman, J.L.
Citation
Journal: J.Med.Chem. / Year: 2006
Title: Complexes of Alkylene-Linked Tacrine Dimers with Torpedo Californica Acetylcholinesterase: Binding of Bis(5)-Tacrine Produces a Dramatic Rearrangement in the Active-Site Gorge.
Authors: Rydberg, E.H. / Brumshtein, B. / Greenblatt, H.M. / Wong, D.M. / Shaya, D. / Williams, L.D. / Carlier, P.R. / Pang, Y.-P. / Silman, I. / Sussman, J.L.
#1: Journal: J.Am.Chem.Soc. / Year: 2003
Title: Acetylcholinesterase Complexed with Bivalent Ligands Related to Huperzine A: Experimental Evidence for Species-Dependent Protein-Ligand Complementarity
Authors: Wong, D.M. / Greenblatt, H.M. / Dvir, H. / Carlier, P.R. / Han, Y.-F. / Pang, Y.-P. / Silman, I. / Sussman, J.L.
#2: Journal: J.Med.Chem. / Year: 1999
Title: Heterodimeric Tacrine-Based Acetylcholinesterase Inhibitors: Investigating Ligand-Peripheral Site Interactions
Authors: Carlier, P.R. / Chow, E.S.-H. / Han, Y.-F. / Liu, J. / El Yazal, J. / Pang, Y.-P.
#3: Journal: J. Comput. Aided Mol. Des. / Year: 1994
Title: Prediction of the Binding Sites of Huperzine a in Acetylcholinesterase by Docking Studies
Authors: Pang, Y.-P. / Kozikowski, A.P.
#4: Journal: Proc.Natl.Acad.Sci.USA / Year: 1993
Title: Quaternary Ligand Binding to Aromatic Residues in the Active-Site Gorge of Acetylcholinesterase
Authors: Harel, M. / Schalk, I. / Ehret-Sabatier, L. / Bouet, F. / Goeldner, M. / Hirth, C. / Axelsen, P.H. / Silman, I. / Sussman, J.L.
#5: 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
DepositionDec 4, 2003Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 21, 2005Provider: repository / Type: Initial release
Revision 1.1Sep 28, 2016Group: Database references / Derived calculations ...Database references / Derived calculations / Non-polymer description / Other / Source and taxonomy / Structure summary / Version format compliance
Revision 1.2Apr 3, 2019Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Experimental preparation / Other
Category: citation / exptl_crystal_grow ...citation / exptl_crystal_grow / pdbx_database_proc / pdbx_database_status / struct_conn
Item: _citation.country / _exptl_crystal_grow.temp ..._citation.country / _exptl_crystal_grow.temp / _pdbx_database_status.recvd_author_approval / _struct_conn.pdbx_leaving_atom_flag
Revision 1.3Jul 29, 2020Group: Data collection / Derived calculations ...Data collection / Derived calculations / Other / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_database_status / pdbx_entity_nonpoly / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_database_status.status_code_sf / _pdbx_entity_nonpoly.name / _struct_conn.pdbx_role
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.4May 12, 2021Group: Derived calculations / Structure summary
Category: chem_comp / pdbx_struct_assembly ...chem_comp / pdbx_struct_assembly / pdbx_struct_assembly_gen / 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 1.5Dec 13, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.6Oct 16, 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)61,5624
Polymers60,7931
Non-polymers7703
Water2,882160
1
A: ACETYLCHOLINESTERASE
hetero molecules

A: ACETYLCHOLINESTERASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)123,1258
Polymers121,5852
Non-polymers1,5406
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_556y,x,-z+11
Unit cell
Length a, b, c (Å)111.193, 111.193, 136.853
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number152
Space group name H-MP3121

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Components

#1: Protein ACETYLCHOLINESTERASE / ACHE


Mass: 60792.516 Da / Num. of mol.: 1 / Source method: isolated from a natural source
Details: SYNTHETIC HETEROBIVALENT TACRINE-BASED DIMER, A8NH2 (N-9-(1', 2', 3', 4'-TETRAHYDROACRIDINYL)-1, 8-DIAMINOOCTANE) DIHYDROCHLORIDE WITH THE TACRINE MOIETY BOUND TO THE 'ANIONIC' SUBSITE, NEAR ...Details: SYNTHETIC HETEROBIVALENT TACRINE-BASED DIMER, A8NH2 (N-9-(1', 2', 3', 4'-TETRAHYDROACRIDINYL)-1, 8-DIAMINOOCTANE) DIHYDROCHLORIDE WITH THE TACRINE MOIETY BOUND TO THE 'ANIONIC' SUBSITE, NEAR THE BOTTOM OF THE ACTIVE SITE GORGE, AND THE 8-AMINO MOIETY BOUND TO THE 'PERIPHERAL' ANIONIC SITE (PAS) AT THE TOP OF THE GORGE OF TCACHE. THE LIGAND, A8NH2, THUS BINDS BY SPANNING THE ACTIVE-SITE GORGE.
Source: (natural) TORPEDO CALIFORNICA (Pacific electric ray)
Organ: ELECTRIC ORGAN / Variant: G2 FORM / Tissue: ELECTROPLAQUE / References: UniProt: P04058, acetylcholinesterase
#2: 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
#3: Chemical ChemComp-A8N / N-9-(1',2',3',4'-TETRAHYDROACRIDINYL)-1,8-DIAMINOOCTANE / (9S)-9-[(8-AMMONIOOCTYL)AMINO]-1,2,3,4,9,10-HEXAHYDROACRIDINIUM


Mass: 327.507 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H33N3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 160 / Source method: isolated from a natural source / Formula: H2O
Compound detailsPROTEIN HYDROLYZES CHOLINE RELEASED INTO THE SYNAPSE. CATALYTIC ACTIVITY: ACETYLCHOLINE + H(2)O = CHOLINE
Has protein modificationY
Sequence detailsTHE SEQUENCE DESCRIBED BELOW IS THAT OF THE T-ISOFORM SPLICE VARIANT OF SWISSPROT ENTRY P04058 AND ...THE SEQUENCE DESCRIBED BELOW IS THAT OF THE T-ISOFORM SPLICE VARIANT OF SWISSPROT ENTRY P04058 AND ANNOTATED IN FTID=VSP_001460 GLU A 536 SWS P04058 ALA 557 THR A 537 SWS P04058 CYS 558

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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: 4.04 Å3/Da / Density % sol: 69.56 %
Crystal growTemperature: 277 K / pH: 5.8
Details: PROTEIN WAS CRYSTALLISED FROM 28-33% V/V PEG 200 0.5M MES PH 5.8 AT 4 DEG. CELSIUS; THEN SOAKED IN MOTHER LIQUOR (40% V/V PEG 200 IN 0.1 M MES BUFFER, PH 5.8) CONTAINING 2MM N-9-(1',2',3',4'- ...Details: PROTEIN WAS CRYSTALLISED FROM 28-33% V/V PEG 200 0.5M MES PH 5.8 AT 4 DEG. CELSIUS; THEN SOAKED IN MOTHER LIQUOR (40% V/V PEG 200 IN 0.1 M MES BUFFER, PH 5.8) CONTAINING 2MM N-9-(1',2',3',4'-TETRAHYDROACRIDINYL) -1,8-DIAMINOOCTANE BIS-HYDROCHLORIDE (A8NH2.2HCL)

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Data collection

DiffractionMean temperature: 120 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5418
DetectorType: RIGAKU IMAGE PLATE / Detector: IMAGE PLATE / Date: Jan 18, 2001 / Details: OSMIC BLUE CONFOCAL MIRRO
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.4→30 Å / Num. obs: 38785 / % possible obs: 97 % / Redundancy: 3.22 % / Biso Wilson estimate: 37.2 Å2 / Rmerge(I) obs: 0.053 / Net I/σ(I): 16.9
Reflection shellResolution: 2.4→2.49 Å / Redundancy: 9.95 % / Rmerge(I) obs: 0.397 / Mean I/σ(I) obs: 2.44 / % possible all: 97.5

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Processing

Software
NameVersionClassification
CNS1.1refinement
DENZOdata reduction
SCALEPACKdata scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2ACE

2ace


Resolution: 2.4→29.14 Å / Rfactor Rfree error: 0.005 / Data cutoff high absF: 1843636.65 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
Details: SEVERAL RESIDUES ARE NOT SEEN IN THE CRYSTAL STRUCTURE, DUE TO DISORDER. THESE INCLUDE ASP A1, ASP A2, HIS A3 AND THE C-TERMINAL RESIDUES AFTER THR A535. SEVERAL RESIDUES MISSING IN CHAIN ...Details: SEVERAL RESIDUES ARE NOT SEEN IN THE CRYSTAL STRUCTURE, DUE TO DISORDER. THESE INCLUDE ASP A1, ASP A2, HIS A3 AND THE C-TERMINAL RESIDUES AFTER THR A535. SEVERAL RESIDUES MISSING IN CHAIN BREAK, FROM HIS A486 - GLU A489 (INCLUSIVE).
RfactorNum. reflection% reflectionSelection details
Rfree0.24 1873 5 %RANDOM
Rwork0.194 ---
obs0.194 37571 96.8 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 38.7999 Å2 / ksol: 0.351354 e/Å3
Displacement parametersBiso mean: 46.7 Å2
Baniso -1Baniso -2Baniso -3
1-9.8 Å27.96 Å20 Å2
2--9.8 Å20 Å2
3----19.61 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.3 Å0.28 Å
Luzzati d res low-5 Å
Luzzati sigma a0.42 Å0.37 Å
Refinement stepCycle: LAST / Resolution: 2.4→29.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4181 0 52 160 4393
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.015
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.7
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d23.9
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d1.19
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.2231.5
X-RAY DIFFRACTIONc_mcangle_it1.9422
X-RAY DIFFRACTIONc_scbond_it2.0592
X-RAY DIFFRACTIONc_scangle_it2.9532.5
LS refinement shellResolution: 2.4→2.49 Å / Rfactor Rfree error: 0.024 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.334 187 5.1 %
Rwork0.309 3504 -
obs--95.7 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2A8N_1.PARA8N.TOP
X-RAY DIFFRACTION3CIS_PEPTIDE.PARAM
X-RAY DIFFRACTION4WATER_REP.PARAM

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