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- PDB-3wb5: Crystal Structure of beta secetase in complex with (6S)-2-amino-3... -

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Basic information

Entry
Database: PDB / ID: 3wb5
TitleCrystal Structure of beta secetase in complex with (6S)-2-amino-3,6-dimethyl-6-[(1R,2R)-2-phenylcyclopropyl]-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 / 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 / protein serine/threonine kinase binding / 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 / late endosome / synaptic vesicle / peptidase activity / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / aspartic-type endopeptidase activity / lysosome / 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-0B4 / IODIDE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.501 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

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Assembly

Deposited unit
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,2938
Polymers46,3931
Non-polymers9007
Water1,31573
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)101.926, 101.926, 168.936
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122

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Components

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Protein , 1 types, 1 molecules A

#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

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Non-polymers , 5 types, 80 molecules

#2: Chemical ChemComp-IOD / IODIDE ION


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


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-0B4 / (6S)-2-amino-3,6-dimethyl-6-[(1R,2R)-2-phenylcyclopropyl]-5,6-dihydropyrimidin-4(3H)-one


Mass: 257.331 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H19N3O
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 73 / 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: 2.73 Å3/Da / Density % sol: 54.95 % / Mosaicity: 0.666 °
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.191M Na3-citrate, 0.133M ammonium iodide, 20.6%(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 11, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 18078 / % possible obs: 96.9 % / Redundancy: 5.1 % / Rmerge(I) obs: 0.105 / Χ2: 1.177 / Net I/σ(I): 8.3
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.5-2.544.90.5578850.7195.9
2.54-2.5950.5128570.732196.1
2.59-2.6450.4638600.738195.3
2.64-2.694.90.4518830.766196.7
2.69-2.7550.4078740.79196.1
2.75-2.8250.3768770.782196.2
2.82-2.895.10.3098800.841196.8
2.89-2.9650.2838710.856196.6
2.96-3.055.10.2278940.936196.9
3.05-3.155.10.1978971.019196.7
3.15-3.265.10.1768851.047197
3.26-3.395.10.1569131.09197.3
3.39-3.555.30.1178951.283197.7
3.55-3.735.30.0949051.441197.3
3.73-3.975.30.0799121.599198
3.97-4.275.20.0689301.657197.9
4.27-4.75.20.0589291.74198
4.7-5.385.10.0559441.779198.3
5.38-6.7850.0579721.612198.1
6.78-504.50.0410151.807194.3

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation3 Å33.36 Å
Translation3 Å33.36 Å

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
PHENIXrefinement
PDB_EXTRACT3.11data extraction
CrystalCleardata collection
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.501→19.693 Å / Occupancy max: 1 / Occupancy min: 0.53 / SU ML: 0.32 / σ(F): 1.38 / Phase error: 23.01 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2607 922 5.11 %RANDOM
Rwork0.2006 ---
obs0.2035 18058 97.31 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 169.46 Å2 / Biso mean: 43.6422 Å2 / Biso min: 14.97 Å2
Refinement stepCycle: LAST / Resolution: 2.501→19.693 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2759 0 38 73 2870
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0042863
X-RAY DIFFRACTIONf_angle_d0.8443890
X-RAY DIFFRACTIONf_chiral_restr0.058425
X-RAY DIFFRACTIONf_plane_restr0.003501
X-RAY DIFFRACTIONf_dihedral_angle_d13.552993
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 7

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.501-2.63240.31541440.25252342248696
2.6324-2.79690.31391330.24722345247896
2.7969-3.01220.28021330.21362395252897
3.0122-3.3140.28251240.2022418254297
3.314-3.79060.25051340.18322446258098
3.7906-4.76450.20661220.16872507262998
4.7645-19.69320.27181320.21332683281599
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)
14.2809-1.4844-1.58442.76571.54812.4757-0.28420.5072-0.2737-0.0946-0.01580.10940.2204-0.04120.21640.3023-0.06990.08340.2536-0.03830.235421.762126.9462-4.2903
24.7481-2.8805-1.68772.69790.89272.66390.31270.490.9297-0.2268-0.1313-0.6803-0.3478-0.2115-0.09460.24740.01270.11850.25020.09470.327910.055549.00494.2335
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid -1 through 143 )A0
2X-RAY DIFFRACTION2chain 'A' and (resid 144 through 385 )A0

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