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- PDB-3wb4: Crystal Structure of beta secetase in complex with 2-amino-3,6-di... -

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Basic information

Entry
Database: PDB / ID: 3wb4
TitleCrystal Structure of beta secetase in complex with 2-amino-3,6-dimethyl-6-(2-phenylethyl)-3,4,5,6-tetrahydropyrimidin-4-one
ComponentsBeta-secretase 1
KeywordsHYDROLASE / PROTEASE 2 / ASP2 / MEMBRANE-ASSOCIATED ASPARTIC PROTEASE 2 / MEMAPSIN-2
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 / prepulse inhibition / amyloid-beta metabolic process ...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 / prepulse inhibition / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / cellular response to copper ion / hippocampal mossy fiber to CA3 synapse / presynaptic modulation of chemical synaptic transmission / multivesicular body / response to lead ion / trans-Golgi network / protein processing / recycling endosome / cellular response to amyloid-beta / positive regulation of neuron apoptotic process / synaptic vesicle / late endosome / amyloid-beta binding / peptidase activity / endopeptidase activity / amyloid fibril formation / lysosome / aspartic-type endopeptidase activity / early endosome / endosome membrane / endosome / membrane raft / Amyloid fiber formation / axon / endoplasmic reticulum lumen / dendrite / neuronal cell body / 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-0B3 / IODIDE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.25 Å
AuthorsYonezawa, S. / Fujiwara, K. / Yamamoto, T. / Hattori, K. / Yamakawa, H. / Muto, C. / Hosono, M. / Tanaka, Y. / Nakano, T. / Takemoto, H. ...Yonezawa, S. / Fujiwara, K. / Yamamoto, T. / Hattori, K. / Yamakawa, H. / Muto, C. / Hosono, M. / Tanaka, Y. / Nakano, T. / Takemoto, H. / Arisawa, M. / Shuto, S.
CitationJournal: Bioorg.Med.Chem. / Year: 2013
Title: Conformational restriction approach to beta-secretase (BACE1) inhibitors III: Effective investigation of the binding mode by combinational use of X-ray analysis, isothermal titration ...Title: Conformational restriction approach to beta-secretase (BACE1) inhibitors III: Effective investigation of the binding mode by combinational use of X-ray analysis, isothermal titration calorimetry and theoretical calculations
Authors: Yonezawa, S. / Fujiwara, K. / Yamamoto, T. / Hattori, K. / Yamakawa, H. / Muto, C. / Hosono, M. / Tanaka, Y. / Nakano, T. / Takemoto, H. / Arisawa, M. / Shuto, S.
History
DepositionMay 13, 2013Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 2, 2013Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2013Group: Database references
Revision 1.2Nov 22, 2017Group: Refinement description / Category: software

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,2618
Polymers46,3931
Non-polymers8687
Water1,820101
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)102.208, 102.208, 169.984
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122

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Components

#1: Protein Beta-secretase 1 / / Aspartyl protease 2 / ASP2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta- ...Aspartyl protease 2 / ASP2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta-site APP cleaving enzyme 1 / Memapsin-2 / Membrane-associated aspartic protease 2


Mass: 46393.043 Da / Num. of mol.: 1 / Fragment: ACTIVE PROTEASE DOMAIN, UNP residues 43-454
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149 / Plasmid: pET28a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P56817, memapsin 2
#2: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-IOD / IODIDE ION / Iodide


Mass: 126.904 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: I
#4: Chemical ChemComp-0B3 / (6R)-2-amino-3,6-dimethyl-6-(2-phenylethyl)-5,6-dihydropyrimidin-4(3H)-one


Mass: 245.320 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H19N3O
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 101 / 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: 2.76 Å3/Da / Density % sol: 55.47 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.164M Na3-citrate, 0.15M ammonium iodide, 22.8%(w/v) PEG5000MME, pH 6.5, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jul 22, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.25→50 Å / Num. obs: 24378 / % possible obs: 95 % / Redundancy: 8 % / Rmerge(I) obs: 0.091 / Net I/σ(I): 8.9
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2.25-2.298.40.501194.4
2.29-2.338.40.493194.5
2.33-2.388.40.427194.7
2.38-2.428.40.414194.8
2.42-2.488.30.381195
2.48-2.538.30.341194.9
2.53-2.68.30.288195.4
2.6-2.678.30.254195.1
2.67-2.758.30.237195.2
2.75-2.838.20.21195.5
2.83-2.948.20.168195.9
2.94-3.058.20.135195.8
3.05-3.198.10.112195.7
3.19-3.368.10.101195.9
3.36-3.5780.073195.8
3.57-3.857.90.057195.3
3.85-4.237.80.048195.3
4.23-4.857.70.041194.9
4.85-6.17.40.039194.5
6.1-506.50.029191

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation3 Å33.46 Å
Translation3 Å33.46 Å

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
PHENIX1.8.1_1168refinement
PDB_EXTRACT3.11data extraction
CrystalCleardata collection
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.25→33.455 Å / Occupancy max: 1 / Occupancy min: 0.43 / SU ML: 0.23 / σ(F): 1.34 / Phase error: 25.09 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.254 1253 5.14 %
Rwork0.2106 --
obs0.2128 24359 95.14 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 40.9914 Å2
Refinement stepCycle: LAST / Resolution: 2.25→33.455 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2709 0 44 101 2854
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0112814
X-RAY DIFFRACTIONf_angle_d1.3523820
X-RAY DIFFRACTIONf_dihedral_angle_d15.056971
X-RAY DIFFRACTIONf_chiral_restr0.094425
X-RAY DIFFRACTIONf_plane_restr0.005490
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.25-2.34010.31761210.22832488X-RAY DIFFRACTION95
2.3401-2.44660.2771400.24372503X-RAY DIFFRACTION95
2.4466-2.57550.27611330.24072522X-RAY DIFFRACTION95
2.5755-2.73680.30531230.24322537X-RAY DIFFRACTION95
2.7368-2.9480.34751330.23982554X-RAY DIFFRACTION96
2.948-3.24450.23791760.21892536X-RAY DIFFRACTION96
3.2445-3.71340.23991540.19252583X-RAY DIFFRACTION96
3.7134-4.67650.21221460.17312623X-RAY DIFFRACTION95
4.6765-33.45910.24621270.21542760X-RAY DIFFRACTION94
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)
15.0969-1.4608-3.15682.3181.15583.413-0.32670.3553-0.57420.1276-0.05740.16130.382-0.1560.17450.2193-0.04540.05410.1725-0.09130.19819.832128.0896-4.343
24.1201-2.3184-2.51361.78851.36383.05070.72330.63941.2114-0.4403-0.2008-0.7528-0.6608-0.2687-0.18560.36320.07950.22910.32090.17680.5019.736751.11511.638
34.9343-3.7002-2.09813.51651.06492.69230.29470.03091.2109-0.1938-0.068-1.147-0.11280.0352-0.00560.1793-0.01870.08670.2432-0.01290.40697.530148.77116.6741
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid -1 through 168 )
2X-RAY DIFFRACTION2chain 'A' and (resid 169 through 282 )
3X-RAY DIFFRACTION3chain 'A' and (resid 283 through 385 )

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