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- PDB-6wuy: Crystal Structure of Recombinant Human Acetylcholinesterase In Co... -

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Basic information

Entry
Database: PDB / ID: 6wuy
TitleCrystal Structure of Recombinant Human Acetylcholinesterase In Complex with GA and HI-6
ComponentsAcetylcholinesterase
KeywordsHYDROLASE / nerve agent / acetylcholinesterase / tabun / GA
Function / homology
Function and homology information


negative regulation of synaptic transmission, cholinergic / Neurotransmitter clearance / acetylcholine catabolic process in synaptic cleft / cholinesterase activity / serine hydrolase activity / acetylcholine catabolic process / acetylcholine binding / amyloid precursor protein metabolic process / acetylcholinesterase / acetylcholine receptor signaling pathway ...negative regulation of synaptic transmission, cholinergic / Neurotransmitter clearance / acetylcholine catabolic process in synaptic cleft / cholinesterase activity / serine hydrolase activity / acetylcholine catabolic process / acetylcholine binding / amyloid precursor protein metabolic process / acetylcholinesterase / acetylcholine receptor signaling pathway / osteoblast development / acetylcholinesterase activity / choline metabolic process / Synthesis of PC / basement membrane / regulation of receptor recycling / Synthesis, secretion, and deacylation of Ghrelin / side of membrane / synaptic cleft / laminin binding / synapse assembly / collagen binding / positive regulation of protein secretion / neuromuscular junction / receptor internalization / : / retina development in camera-type eye / nervous system development / positive regulation of cold-induced thermogenesis / amyloid-beta binding / hydrolase activity / cell adhesion / synapse / perinuclear region of cytoplasm / Golgi apparatus / cell surface / protein homodimerization activity / extracellular space / extracellular region / membrane / nucleus / 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
ethoxy-~{N},~{N}-dimethyl-phosphonamidic acid / Chem-HI6 / Acetylcholinesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.46 Å
AuthorsMcGuire, J.R. / Bester, S.M. / Pegan, S.D. / Height, J.J.
Funding support United States, 1items
OrganizationGrant numberCountry
Defense Threat Reduction Agency (DTRA)CB#3889 United States
CitationJournal: Chem.Res.Toxicol. / Year: 2021
Title: Structural and Biochemical Insights into the Inhibition of Human Acetylcholinesterase by G-Series Nerve Agents and Subsequent Reactivation by HI-6.
Authors: McGuire, J.R. / Bester, S.M. / Guelta, M.A. / Cheung, J. / Langley, C. / Winemiller, M.D. / Bae, S.Y. / Funk, V. / Myslinski, J.M. / Pegan, S.D. / Height, J.J.
History
DepositionMay 5, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 17, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 31, 2021Group: 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
Revision 1.2Oct 18, 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Acetylcholinesterase
B: Acetylcholinesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)121,56410
Polymers118,8942
Non-polymers2,6708
Water4,918273
1
A: Acetylcholinesterase
hetero molecules

B: Acetylcholinesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)121,56410
Polymers118,8942
Non-polymers2,6708
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_557y,x,-z+21
Buried area5160 Å2
ΔGint22 kcal/mol
Surface area38510 Å2
MethodPISA
Unit cell
Length a, b, c (Å)105.331, 105.331, 324.866
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Acetylcholinesterase / AChE


Mass: 59447.105 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACHE / Production host: Homo sapiens (human) / References: UniProt: P22303, acetylcholinesterase

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Sugars , 3 types, 4 molecules

#2: 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-ROHGlycam 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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}[(6+1)][a-L-Fucp]{}}LINUCSPDB-CARE
#3: 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-ROHGlycam 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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}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.: 1
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

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Non-polymers , 3 types, 277 molecules

#5: Chemical ChemComp-ELT / ethoxy-~{N},~{N}-dimethyl-phosphonamidic acid


Mass: 153.117 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H12NO3P / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-HI6 / 4-(AMINOCARBONYL)-1-[({2-[(E)-(HYDROXYIMINO)METHYL]PYRIDINIUM-1-YL}METHOXY)METHYL]PYRIDINIUM / 1-(2-HYDROXY-IMINOMETHYLPYRIDINIUM)-1-(4-CARBOXYAMINO)-PYRIDINIUM DIMETHYLETHER


Mass: 288.302 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H16N4O3 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 273 / 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: 4.38 Å3/Da / Density % sol: 71.89 % / Mosaicity: 0.435 °
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: PEG 3350, KNO3

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Aug 11, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.46→50 Å / Num. obs: 77513 / % possible obs: 99.8 % / Redundancy: 6 % / Biso Wilson estimate: 55.53 Å2 / Rmerge(I) obs: 0.071 / Rpim(I) all: 0.031 / Rrim(I) all: 0.078 / Χ2: 0.749 / Net I/σ(I): 8.4
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.46-2.55.20.63937880.8960.3060.710.60699.4
2.5-2.5560.61438100.9310.2720.6720.58999.9
2.55-2.66.10.53938280.9510.2370.590.61100
2.6-2.656.10.46338580.9620.2050.5070.651100
2.65-2.7160.46338370.9560.2070.5080.896100
2.71-2.776.10.3338090.9760.1460.3610.715100
2.77-2.8460.27338240.980.1210.2990.734100
2.84-2.9260.21838590.9880.0970.2390.77699.9
2.92-360.17638440.9920.0790.1930.79599.9
3-3.160.14138570.9940.0630.1550.879100
3.1-3.216.10.12338470.9950.0540.1340.882100
3.21-3.346.20.10438380.9940.0460.1140.93499.9
3.34-3.496.20.10338770.9960.0450.1131.028100
3.49-3.676.20.08438900.9960.0370.0920.862100
3.67-3.96.20.07338560.9970.0320.0790.81299.8
3.9-4.216.10.05739000.9970.0250.0630.64499.4
4.21-4.636.10.05339020.9980.0230.0580.61699.6
4.63-5.36.10.05239350.9970.0230.0560.59899.5
5.3-6.6760.04440040.9980.020.0480.68899.9
6.67-505.70.03441500.9990.0160.0380.64398.5

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Processing

Software
NameVersionClassification
HKL-2000data reduction
HKL-2000data scaling
PHENIX1.17.1-3660refinement
PDB_EXTRACT3.25data extraction
PHENIX1.17.1-3660phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4EY4

4ey4


Resolution: 2.46→41.364 Å / SU ML: 0.28 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 25.54 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2144 3770 4.88 %
Rwork0.179 73540 -
obs0.1807 77310 99.5 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 152.13 Å2 / Biso mean: 66.1735 Å2 / Biso min: 30 Å2
Refinement stepCycle: final / Resolution: 2.46→41.364 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8250 0 197 273 8720
Biso mean--109.4 63.19 -
Num. residues----1061
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0058847
X-RAY DIFFRACTIONf_angle_d0.89612120
X-RAY DIFFRACTIONf_chiral_restr0.0531303
X-RAY DIFFRACTIONf_plane_restr0.0061587
X-RAY DIFFRACTIONf_dihedral_angle_d7.4047018
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.46-2.48320.361340.2899254395
2.4832-2.51580.29821420.26382695100
2.5158-2.55030.29591380.24432709100
2.5503-2.58670.27711340.242665100
2.5867-2.62530.27311400.23452716100
2.6253-2.66630.3111400.2413264499
2.6663-2.71010.28651670.24312689100
2.7101-2.75680.28771580.23122676100
2.7568-2.80690.27321380.23182695100
2.8069-2.86090.31311450.22642695100
2.8609-2.91920.28781460.23532700100
2.9192-2.98270.29071310.22812706100
2.9827-3.05210.27381420.22152701100
3.0521-3.12840.31711200.21242734100
3.1284-3.21290.2811260.20722738100
3.2129-3.30740.23871350.20722714100
3.3074-3.41410.22281490.2032709100
3.4141-3.53610.26421140.20042755100
3.5361-3.67760.23521190.17732737100
3.6776-3.84490.20691580.16622716100
3.8449-4.04740.18091270.1504277799
4.0474-4.30070.16041300.14622721100
4.3007-4.63240.1581590.13022752100
4.6324-5.09780.16831480.135277199
5.0978-5.83370.1861650.15542783100
5.8337-7.34320.19561240.17092850100
7.3432-41.3640.17451410.1657294998

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