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- PDB-5uyu: Crystal structure of BACE1 in complex with 2-aminooxazoline-3-aza... -

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Basic information

Entry
Database: PDB / ID: 5uyu
TitleCrystal structure of BACE1 in complex with 2-aminooxazoline-3-azaxanthene compound 12
ComponentsBeta-secretase 1
KeywordsHYDROLASE / aspartic protease / Alzheimers disease / APP / amyloid precursor protein
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 / detection of mechanical stimulus involved in sensory perception of pain / amyloid-beta metabolic process / cellular response to manganese ion ...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 / detection of mechanical stimulus involved in sensory perception of pain / amyloid-beta metabolic process / cellular response to manganese ion / prepulse inhibition / protein serine/threonine kinase binding / cellular response to copper ion / presynaptic modulation of chemical synaptic transmission / multivesicular body / hippocampal mossy fiber to CA3 synapse / response to lead ion / trans-Golgi network / recycling endosome / protein processing / positive regulation of neuron apoptotic process / cellular response to amyloid-beta / late endosome / synaptic vesicle / 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-8QV / IODIDE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsWhittington, D.A. / Long, A.M. / Sickmier, E.A.
CitationJournal: Medchemcomm / Year: 2017
Title: Development of 2-aminooxazoline 3-azaxanthene beta-amyloid cleaving enzyme (BACE) inhibitors with improved selectivity against Cathepsin D.
Authors: Low, J.D. / Bartberger, M.D. / Chen, K. / Cheng, Y. / Fielden, M.R. / Gore, V. / Hickman, D. / Liu, Q. / Allen Sickmier, E. / Vargas, H.M. / Werner, J. / White, R.D. / Whittington, D.A. / ...Authors: Low, J.D. / Bartberger, M.D. / Chen, K. / Cheng, Y. / Fielden, M.R. / Gore, V. / Hickman, D. / Liu, Q. / Allen Sickmier, E. / Vargas, H.M. / Werner, J. / White, R.D. / Whittington, D.A. / Wood, S. / Minatti, A.E.
History
DepositionFeb 24, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 17, 2017Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2017Group: Refinement description / Category: software
Revision 1.2Aug 29, 2018Group: Data collection / Database references / Derived calculations
Category: citation / citation_author / pdbx_struct_special_symmetry
Item: _citation.journal_id_ISSN / _citation.journal_volume ..._citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.3Oct 4, 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)47,0008
Polymers45,8221
Non-polymers1,1777
Water6,666370
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)102.287, 102.287, 170.374
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-738-

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: R5K, R4K
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


Mass: 126.904 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: I
#3: Chemical ChemComp-8QV / (5S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-[5-(prop-1-yn-1-yl)pyridin-3-yl]-5'H-spiro[1-benzopyrano[2,3-c]pyridine-5,4'-[1,3]oxazol]-2'-amine


Mass: 450.489 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H22N4O3
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 370 / 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: 56.19 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 6.6
Details: 21% polyethylene glycol 5000 MME, 180 mM sodium citrate (pH 6.6), 200 mM ammonium iodide, 3% (v/v) DMSO

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Feb 19, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. obs: 41991 / % possible obs: 99.4 % / Observed criterion σ(I): -3 / Redundancy: 6.8 % / Rmerge(I) obs: 0.071 / Χ2: 1.027 / Net I/av σ(I): 17.2 / Net I/σ(I): 15.3
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allΧ2% possible all
1.9-1.9730.4532.439351.00195
1.97-2.054.30.3390.94799.3
2.05-2.146.70.2741.002100
2.14-2.257.70.2080.992100
2.25-2.397.80.1570.987100
2.39-2.587.80.1220.957100
2.58-2.847.80.090.921100
2.84-3.257.90.0650.859100
3.25-4.097.80.0530.802100
4.09-507.40.051.73299.7

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Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMACrefinement
PDB_EXTRACT3.22data extraction
HKL-2000data reduction
AMoREphasing
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1W50

1w50


Resolution: 1.9→50 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.941 / SU B: 5.922 / SU ML: 0.101 / SU R Cruickshank DPI: 0.1409 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.141 / ESU R Free: 0.128
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES: WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.228 2116 5 %RANDOM
Rwork0.2052 ---
obs0.2064 39815 99.42 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 112.35 Å2 / Biso mean: 29.7 Å2 / Biso min: 13.72 Å2
Baniso -1Baniso -2Baniso -3
1--0.25 Å2-0.13 Å20 Å2
2---0.25 Å20 Å2
3---0.38 Å2
Refinement stepCycle: final / Resolution: 1.9→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2914 0 45 370 3329
Biso mean--28.91 36.12 -
Num. residues----370
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.023035
X-RAY DIFFRACTIONr_bond_other_d0.0010.022037
X-RAY DIFFRACTIONr_angle_refined_deg1.2581.9614127
X-RAY DIFFRACTIONr_angle_other_deg0.8353.0044908
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3675367
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.70523.723137
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.21415476
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.1981517
X-RAY DIFFRACTIONr_chiral_restr0.0680.2444
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0213379
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02647
LS refinement shellResolution: 1.9→1.949 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.41 129 -
Rwork0.392 2527 -
all-2656 -
obs--93.52 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.62230.97351.18722.18040.67091.5943-0.2073-0.09140.1687-0.13150.01790.1335-0.1770.00060.18940.09140.0327-0.05360.0245-0.01620.038571.491161.06145.3411
24.12291.88861.10072.57150.17982.18150.0717-0.1324-0.4760.10030.0192-0.28010.0633-0.1112-0.09090.08450.0123-0.04710.01230.00530.07557.960143.073-2.3633
32.55450.73181.16692.9093-0.33882.15770.22130.034-0.91460.22950.0503-1.18080.33360.3371-0.27160.17120.0101-0.16440.1135-0.03650.646766.738929.5102-3.0756
43.31082.13871.70663.60440.06441.4504-0.02930.1125-0.40680.00680.1378-0.46510.0091-0.061-0.10850.072-0.0266-0.01820.0955-0.03290.078657.075542.1809-7.3779
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A-1 - 147
2X-RAY DIFFRACTION2A148 - 239
3X-RAY DIFFRACTION3A240 - 328
4X-RAY DIFFRACTION4A329 - 385

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