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- PDB-3skg: Crystal structure of beta-site app-cleaving enzyme 1 (BACE-WT) co... -

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Basic information

Entry
Database: PDB / ID: 3skg
TitleCrystal structure of beta-site app-cleaving enzyme 1 (BACE-WT) complex with (2S)-2-((3R)-3-acetamido-3-isobutyl-2-oxo-1-pyrrolidinyl)-N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-2-(1,2,3,4-tetrahydro-3-isoquinolinyl)ethyl)-4-phenylbutanamide
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Alzheimer's disease / BACE / 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 / 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-PB8 / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.88 Å
AuthorsMuckelbauer, J.K.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Synthesis and in vivo evaluation of cyclic diaminopropane BACE-1 inhibitors.
Authors: Thompson, L.A. / Shi, J. / Decicco, C.P. / Tebben, A.J. / Olson, R.E. / Boy, K.M. / Guernon, J.M. / Good, A.C. / Liauw, A. / Zheng, C. / Copeland, R.A. / Combs, A.P. / Trainor, G.L. / Camac, ...Authors: Thompson, L.A. / Shi, J. / Decicco, C.P. / Tebben, A.J. / Olson, R.E. / Boy, K.M. / Guernon, J.M. / Good, A.C. / Liauw, A. / Zheng, C. / Copeland, R.A. / Combs, A.P. / Trainor, G.L. / Camac, D.M. / Muckelbauer, J.K. / Lentz, K.A. / Grace, J.E. / Burton, C.R. / Toyn, J.H. / Barten, D.M. / Marcinkeviciene, J. / Meredith, J.E. / Albright, C.F. / Macor, J.E.
History
DepositionJun 22, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 7, 2011Provider: repository / Type: Initial release
Revision 1.1Oct 19, 2011Group: Database references
Revision 1.2Nov 2, 2011Group: Database references
Revision 1.3Dec 5, 2012Group: Database references

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Beta-secretase 1
B: Beta-secretase 1
D: Beta-secretase 1
E: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)203,5258
Polymers200,8824
Non-polymers2,6434
Water1,910106
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,8812
Polymers50,2201
Non-polymers6611
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,8812
Polymers50,2201
Non-polymers6611
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
D: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,8812
Polymers50,2201
Non-polymers6611
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
E: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,8812
Polymers50,2201
Non-polymers6611
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)86.240, 130.451, 86.872
Angle α, β, γ (deg.)90.00, 96.65, 90.00
Int Tables number4
Space group name H-MP1211

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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: 50220.492 Da / Num. of mol.: 4 / Fragment: UNP residues 14-454
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-PB8 / (2S)-2-[(3R)-3-(acetylamino)-3-(2-methylpropyl)-2-oxopyrrolidin-1-yl]-N-{(1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-[(3R)-1,2,3,4-tetrahydroisoquinolin-3-yl]propan-2-yl}-4-phenylbutanamide


Mass: 660.793 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C38H46F2N4O4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 106 / 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: 2.42 Å3/Da / Density % sol: 49.09 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.2
Details: pH 6.2, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ DW / Wavelength: 1.541
DetectorType: RIGAKU SATURN 92 / Detector: CCD / Date: Jun 10, 2009 / Details: MICROMAX CONFOCAL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.541 Å / Relative weight: 1
ReflectionRedundancy: 5.9 % / Av σ(I) over netI: 11.32 / Number: 251674 / Rmerge(I) obs: 0.172 / Χ2: 1.09 / D res high: 2.9 Å / D res low: 50 Å / Num. obs: 42876 / % possible obs: 99.9
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)% possible obs (%)IDRmerge(I) obsChi squaredRedundancy
6.245099.210.0931.5155.7
4.966.2410010.1161.0676
4.334.9610010.1161.5846
3.944.3310010.1331.2276
3.653.9410010.1511.2465.9
3.443.6510010.1860.9235.9
3.273.4410010.2530.8535.9
3.123.2710010.3480.9545.8
33.1210010.4310.7615.8
2.9310010.5320.7225.8
ReflectionResolution: 2.878→30.628 Å / Num. obs: 42876 / % possible obs: 99.9 % / Redundancy: 5.9 % / Rmerge(I) obs: 0.172 / Net I/σ(I): 4.6
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2.9-35.80.5321100
3-3.125.80.4311100
3.12-3.275.80.3481100
3.27-3.445.90.2531100
3.44-3.655.90.1861100
3.65-3.945.90.1511100
3.94-4.3360.1331100
4.33-4.9660.1161100
4.96-6.2460.1161100
6.24-505.70.093199.2

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
REFMAC5.2.0019refinement
PDB_EXTRACT3.1data extraction
CrystalCleardata collection
HKL-2000data reduction
HKL-2000data scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.88→30.628 Å / Cor.coef. Fo:Fc: 0.868 / Cor.coef. Fo:Fc free: 0.757 / Occupancy max: 1 / Occupancy min: 1 / SU B: 23.461 / SU ML: 0.462 / Cross valid method: THROUGHOUT / ESU R Free: 0.566 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.34813 2159 5 %RANDOM
Rwork0.25467 ---
obs0.25943 40650 98.77 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.53 Å2
Baniso -1Baniso -2Baniso -3
1--2.42 Å20 Å20.24 Å2
2---3.1 Å20 Å2
3---5.57 Å2
Refinement stepCycle: LAST / Resolution: 2.88→30.628 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12136 0 192 106 12434
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0290.02212667
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.5041.96417246
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.83551540
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.11823.916572
X-RAY DIFFRACTIONr_dihedral_angle_3_deg21.663151980
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.5291568
X-RAY DIFFRACTIONr_chiral_restr0.1510.21900
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.029744
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2740.26494
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3330.28319
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2260.2568
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.3040.294
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1820.26
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.45428020
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.2692.512396
X-RAY DIFFRACTIONr_scbond_it2.48435534
X-RAY DIFFRACTIONr_scangle_it3.6414.54850
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.878→2.953 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.495 142 -
Rwork0.294 2615 -
obs--86.24 %

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