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- PDB-3s7l: Pyrazolyl and Thienyl Aminohydantoins as Potent BACE1 Inhibitors -

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Basic information

Entry
Database: PDB / ID: 3s7l
TitlePyrazolyl and Thienyl Aminohydantoins as Potent BACE1 Inhibitors
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Aspartyl protease / Disulfide bond / Protease / 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 / 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-591 / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.162 Å
AuthorsChopra, R. / Olland, A. / Svenson, K.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: New pyrazolyl and thienyl aminohydantoins as potent BACE1 inhibitors: Exploring the S2' region.
Authors: Malamas, M.S. / Erdei, J. / Gunawan, I. / Barnes, K. / Hui, Y. / Johnson, M. / Robichaud, A. / Zhou, P. / Yan, Y. / Solvibile, W. / Turner, J. / Fan, K.Y. / Chopra, R. / Bard, J. / Pangalos, M.N.
History
DepositionMay 26, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 31, 2011Provider: repository / Type: Initial release

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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)46,8022
Polymers46,4411
Non-polymers3611
Water2,666148
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)72.835, 103.749, 50.411
Angle α, β, γ (deg.)90.0, 94.82, 90.0
Int Tables number5
Space group name H-MC121

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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: 46440.980 Da / Num. of mol.: 1 / Fragment: UNP residues 46-454
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-591 / (5S)-2-amino-5-(1-ethyl-1H-pyrazol-4-yl)-3-methyl-5-[3-(pyrimidin-5-yl)phenyl]-3,5-dihydro-4H-imidazol-4-one / WAY-256591


Mass: 361.400 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H19N7O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 148 / 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: 2.04 Å3/Da / Density % sol: 39.81 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 5.4
Details: 10-15% PEG 3350, 100 mM NaAcetate pH 5.4, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.54 Å
DetectorType: BRUKER SMART 6000 / Detector: CCD / Date: Jan 20, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.162→20 Å / Num. all: 19656 / Num. obs: 17193 / % possible obs: 87 % / Observed criterion σ(F): 1.5 / Observed criterion σ(I): 1.5
Reflection shellResolution: 2.1621→2.2393 Å / % possible all: 17

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Processing

Software
NameClassification
CrystalCleardata collection
PHENIXmodel building
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.162→19.95 Å / Occupancy max: 1 / Occupancy min: 1 / SU ML: 0.02 / σ(F): 0 / Phase error: 25.13 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2273 892 5.19 %5%
Rwork0.1744 16298 --
obs0.1771 17190 86.11 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 36.245 Å2 / ksol: 0.341 e/Å3
Displacement parametersBiso max: 96.16 Å2 / Biso mean: 33.0364 Å2 / Biso min: 8.11 Å2
Baniso -1Baniso -2Baniso -3
1--3.8785 Å2-0 Å2-7.777 Å2
2---6.052 Å20 Å2
3---8.2662 Å2
Refinement stepCycle: LAST / Resolution: 2.162→19.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2889 0 27 148 3064
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0112994
X-RAY DIFFRACTIONf_angle_d1.2664067
X-RAY DIFFRACTIONf_chiral_restr0.069443
X-RAY DIFFRACTIONf_plane_restr0.005520
X-RAY DIFFRACTIONf_dihedral_angle_d17.2511053
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 6

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.1621-2.29740.3165580.2181980103831
2.2974-2.47450.2631470.19562770291789
2.4745-2.7230.26641820.18283057323998
2.723-3.11570.22791620.18013132329499
3.1157-3.92050.21411830.167331453328100
3.9205-19.95130.1961600.157732143374100

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