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- PDB-4wtu: Crystal structure of BACE1 in complex with 2-aminooxazoline 3-aza... -

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Basic information

Entry
Database: PDB / ID: 4wtu
TitleCrystal structure of BACE1 in complex with 2-aminooxazoline 3-aza-4-fluoro-xanthene inhibitor 22
ComponentsBeta-secretase 1
KeywordsHydrolase/Hydrolase Inhibitor / aspartic protease / amyloid precursor protein / Alzheimer's disease / Hydrolase-Hydrolase Inhibitor complex
Function / homology
Function and homology information


memapsin 2 / Golgi-associated vesicle lumen / signaling receptor ligand precursor processing / beta-aspartyl-peptidase activity / amyloid precursor protein catabolic process / amyloid-beta formation / membrane protein ectodomain proteolysis / cellular response to manganese ion / amyloid-beta metabolic process / prepulse inhibition ...memapsin 2 / Golgi-associated vesicle lumen / signaling receptor ligand precursor processing / beta-aspartyl-peptidase activity / amyloid precursor protein catabolic process / amyloid-beta formation / membrane protein ectodomain proteolysis / cellular response to manganese ion / amyloid-beta metabolic process / prepulse inhibition / detection of mechanical stimulus involved in sensory perception of pain / cellular response to copper ion / presynaptic modulation of chemical synaptic transmission / hippocampal mossy fiber to CA3 synapse / multivesicular body / response to lead ion / trans-Golgi network / recycling endosome / protein processing / cellular response to amyloid-beta / positive regulation of neuron apoptotic process / synaptic vesicle / late endosome / peptidase activity / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / lysosome / aspartic-type endopeptidase activity / early endosome / endosome membrane / endosome / membrane raft / Amyloid fiber formation / endoplasmic reticulum lumen / axon / neuronal cell body / dendrite / Golgi apparatus / enzyme binding / cell surface / proteolysis / membrane / plasma membrane
Similarity search - Function
Beta-secretase BACE1 / Beta-secretase BACE / Memapsin-like / Eukaryotic aspartyl protease / Aspartic peptidase A1 family / Peptidase family A1 domain / Peptidase family A1 domain profile. / Cathepsin D, subunit A; domain 1 / Acid Proteases / Aspartic peptidase, active site ...Beta-secretase BACE1 / Beta-secretase BACE / Memapsin-like / Eukaryotic aspartyl protease / Aspartic peptidase A1 family / Peptidase family A1 domain / Peptidase family A1 domain profile. / Cathepsin D, subunit A; domain 1 / Acid Proteases / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Chem-3UT / IODIDE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.85 Å
AuthorsWhittington, D.A. / Long, A.M.
CitationJournal: Acs Med.Chem.Lett. / Year: 2015
Title: An Orally Available BACE1 Inhibitor That Affords Robust CNS A beta Reduction without Cardiovascular Liabilities.
Authors: Cheng, Y. / Brown, J. / Judd, T.C. / Lopez, P. / Qian, W. / Powers, T.S. / Chen, J.J. / Bartberger, M.D. / Chen, K. / Dunn, R.T. / Epstein, O. / Fremeau, R.T. / Harried, S. / Hickman, D. / ...Authors: Cheng, Y. / Brown, J. / Judd, T.C. / Lopez, P. / Qian, W. / Powers, T.S. / Chen, J.J. / Bartberger, M.D. / Chen, K. / Dunn, R.T. / Epstein, O. / Fremeau, R.T. / Harried, S. / Hickman, D. / Hitchcock, S.A. / Luo, Y. / Minatti, A.E. / Patel, V.F. / Vargas, H.M. / Wahl, R.C. / Weiss, M.M. / Wen, P.H. / White, R.D. / Whittington, D.A. / Zheng, X.M. / Wood, S.
History
DepositionOct 30, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 4, 2015Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2017Group: Derived calculations / Other ...Derived calculations / Other / Refinement description / Source and taxonomy
Category: entity_src_gen / pdbx_database_status ...entity_src_gen / pdbx_database_status / pdbx_struct_oper_list / software
Item: _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_oper_list.symmetry_operation
Revision 1.2Sep 27, 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

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Assembly

Deposited unit
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,9638
Polymers45,8221
Non-polymers1,1407
Water7,710428
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)102.136, 102.136, 171.425
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122
Components on special symmetry positions
IDModelComponents
11A-525-

HOH

21A-557-

HOH

31A-590-

HOH

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Components

#1: Protein Beta-secretase 1 / / Aspartyl protease 2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta-site APP ...Aspartyl protease 2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta-site APP cleaving enzyme 1 / Memapsin-2 / Membrane-associated aspartic protease 2


Mass: 45822.445 Da / Num. of mol.: 1 / Fragment: UNP residues 43-453 / Mutation: R56K, R57K
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149 / Production host: Escherichia coli (E. coli) / References: UniProt: P56817, memapsin 2
#2: Chemical
ChemComp-IOD / IODIDE ION / Iodide


Mass: 126.904 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: I
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-3UT / (5S)-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-7-(2-fluoropyridin-3-yl)spiro[chromeno[2,3-c]pyridine-5,4'-[1,3]oxazol]-2'-amine


Mass: 448.422 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H18F2N4O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 428 / 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: 2.81 Å3/Da / Density % sol: 56.27 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.6
Details: 21% PEG 5000 MME, 190 mM sodium citrate, 200 mM ammonium iodide

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Mar 27, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.85→50 Å / Num. obs: 45811 / % possible obs: 100 % / Observed criterion σ(I): -3 / Redundancy: 9.6 % / Biso Wilson estimate: 26.77 Å2 / Rmerge(I) obs: 0.088 / Χ2: 1.023 / Net I/av σ(I): 24.2 / Net I/σ(I): 15 / Num. measured all: 440197
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Mean I/σ(I) obsNum. unique allΧ2% possible allRmerge(I) obs
1.85-1.929.72.344770.894100
1.92-1.999.744870.9081000.681
1.99-2.089.745020.9661000.474
2.08-2.199.745080.9781000.336
2.19-2.339.745201.0061000.256
2.33-2.519.745311.0311000.199
2.51-2.769.745810.9671000.135
2.76-3.169.746011.1881000.091
3.16-3.999.546621.2541000.062
3.99-50949421.03199.80.038

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Processing

Software
NameVersionClassification
HKL-2000data reduction
REFMAC5.6.0117refinement
PDB_EXTRACT3.15data extraction
HKL-2000data scaling
DENZOdata reduction
SCALEPACKdata scaling
REFMAC5.6.0117phasing
RefinementStarting model: PDB entry 4FRK

4frk


Resolution: 1.85→48.97 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.958 / WRfactor Rfree: 0.1877 / WRfactor Rwork: 0.164 / FOM work R set: 0.8885 / SU B: 2.285 / SU ML: 0.068 / SU R Cruickshank DPI: 0.1075 / SU Rfree: 0.103 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.108 / ESU R Free: 0.103 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.1957 2282 5 %RANDOM
Rwork0.1693 43462 --
obs0.1706 45744 99.98 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 89.14 Å2 / Biso mean: 26.24 Å2 / Biso min: 15.22 Å2
Baniso -1Baniso -2Baniso -3
1-0.01 Å20 Å20 Å2
2--0.01 Å20 Å2
3----0.01 Å2
Refinement stepCycle: final / Resolution: 1.85→48.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2923 0 49 428 3400
Biso mean--27.4 41.49 -
Num. residues----371
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.023048
X-RAY DIFFRACTIONr_bond_other_d0.0010.022048
X-RAY DIFFRACTIONr_angle_refined_deg1.2281.9634144
X-RAY DIFFRACTIONr_angle_other_deg0.8183.0044936
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2985368
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.06123.768138
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.92615478
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.581517
X-RAY DIFFRACTIONr_chiral_restr0.0730.2446
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0213389
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02648
LS refinement shellResolution: 1.85→1.898 Å
RfactorNum. reflection% reflection
Rfree0.293 147 -
Rwork0.258 2853 -
obs--100 %

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