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- PDB-3u6a: Rational Design and Synthesis of Aminopiperazinones as Beta Secre... -

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Basic information

Entry
Database: PDB / ID: 3u6a
TitleRational Design and Synthesis of Aminopiperazinones as Beta Secretase (BACE) Inhibitors
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / beta-site APP cleaving enzyme 1 / 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-18P / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.199 Å
AuthorsSpurlino, J.C. / Alexander, R.S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Rational design and synthesis of aminopiperazinones as beta-secretase (BACE) inhibitors.
Authors: Tresadern, G. / Delgado, F. / Delgado, O. / Gijsen, H. / Macdonald, G.J. / Moechars, D. / Rombouts, F. / Alexander, R. / Spurlino, J. / Van Gool, M. / Vega, J.A. / Trabanco, A.A.
History
DepositionOct 12, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 9, 2011Provider: repository / Type: Initial release
Revision 1.1Sep 4, 2013Group: Database references

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Beta-secretase 1
B: Beta-secretase 1
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)132,13215
Polymers130,1523
Non-polymers1,98012
Water12,160675
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,0445
Polymers43,3841
Non-polymers6604
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,1406
Polymers43,3841
Non-polymers7565
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,9484
Polymers43,3841
Non-polymers5643
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)225.300, 104.450, 66.760
Angle α, β, γ (deg.)90.00, 102.66, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11C-397-

HOH

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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: 43383.883 Da / Num. of mol.: 3 / Fragment: UNP residues 58-446
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-18P / N-{3-[(2R)-6-amino-2,4-dimethyl-3-oxo-2,3,4,5-tetrahydropyrazin-2-yl]phenyl}-5-chloropyridine-2-carboxamide


Mass: 371.821 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C18H18ClN5O2
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 675 / 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: 2.94 Å3/Da / Density % sol: 58.22 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 8
Details: 100mM Sodium Citrate pH 5.4-6.0, 200mM NH4I, 16% PEG5000mme, VAPOR DIFFUSION, temperature 293K

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Data collection

DiffractionMean temperature: 77 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 13, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. obs: 73495 / % possible obs: 91.3 %

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Processing

SoftwareName: PHENIX / Version: (phenix.refine: 1.7.1_743) / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.199→38.023 Å / SU ML: 0.61 / σ(F): 1.99 / Phase error: 27.3 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.237 2011 2.74 %random
Rwork0.1871 ---
obs0.1885 73486 95.75 %-
Solvent computationShrinkage radii: 0.95 Å / VDW probe radii: 1.2 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 32.516 Å2 / ksol: 0.33 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--7.0126 Å20 Å2-6.6971 Å2
2---9.449 Å2-0 Å2
3---16.4616 Å2
Refinement stepCycle: LAST / Resolution: 2.199→38.023 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8955 0 123 675 9753
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0089321
X-RAY DIFFRACTIONf_angle_d1.15412673
X-RAY DIFFRACTIONf_dihedral_angle_d17.4173361
X-RAY DIFFRACTIONf_chiral_restr0.0771364
X-RAY DIFFRACTIONf_plane_restr0.0051630
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1986-2.25350.27951340.21874645X-RAY DIFFRACTION87
2.2535-2.31450.27391370.20895097X-RAY DIFFRACTION96
2.3145-2.38260.29781360.19725200X-RAY DIFFRACTION97
2.3826-2.45940.27591560.21015026X-RAY DIFFRACTION96
2.4594-2.54730.32591390.20855136X-RAY DIFFRACTION97
2.5473-2.64930.32611370.21125172X-RAY DIFFRACTION97
2.6493-2.76980.26231490.20545124X-RAY DIFFRACTION96
2.7698-2.91580.23881510.20185150X-RAY DIFFRACTION97
2.9158-3.09840.23531450.19095143X-RAY DIFFRACTION97
3.0984-3.33750.24071500.18845177X-RAY DIFFRACTION97
3.3375-3.67320.19921400.17415135X-RAY DIFFRACTION96
3.6732-4.20410.18651380.15915065X-RAY DIFFRACTION95
4.2041-5.29440.19841460.15215142X-RAY DIFFRACTION96
5.2944-38.02870.23271530.2085263X-RAY DIFFRACTION97

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