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

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Basic information

Entry
Database: PDB / ID: 3skf
TitleCrystal structure of beta-site app-cleaving enzyme 1 (BACE-WT) complex with (2S)-2-((3S)-3-(acetylamino)-3-(butan-2-yl)-2-oxopyrrolidin-1-yl)-N-((2S,3R)-3-hydroxy-4-((3-methoxybenzyl)amino)-1-phenylbutan-2-yl)-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 / 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 / multivesicular body / hippocampal mossy fiber to CA3 synapse / 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 / early endosome / lysosome / 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
IODIDE ION / Chem-PB7 / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 3 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 1.0Aug 31, 2011Provider: repository / Type: Initial release
Revision 1.1Oct 19, 2011Group: Database references
Revision 1.2Nov 2, 2011Group: 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)101,9806
Polymers100,4412
Non-polymers1,5394
Water3,387188
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,9903
Polymers50,2201
Non-polymers7702
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,9903
Polymers50,2201
Non-polymers7702
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)90.288, 130.264, 85.871
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22B

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1112A-5 - 385
2112B-5 - 385
1121A394
2121B394

NCS ensembles :
ID
1
2

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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.: 2 / 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-PB7 / (2S)-2-{(3S)-3-(acetylamino)-3-[(2S)-butan-2-yl]-2-oxopyrrolidin-1-yl}-N-{(2S,3R)-3-hydroxy-4-[(3-methoxybenzyl)amino]-1-phenylbutan-2-yl}-4-phenylbutanamide


Mass: 642.827 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C38H50N4O5
#3: Chemical ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: I
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 188 / 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: 2.51 Å3/Da / Density % sol: 51.07 %
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: Sep 4, 2003 / Details: MICROMAX CONFOCAL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.541 Å / Relative weight: 1
ReflectionResolution: 3→34.06 Å / Num. obs: 20761 / % possible obs: 99.9 % / Redundancy: 7.2 % / Rmerge(I) obs: 0.229 / Χ2: 0.989 / Net I/σ(I): 3.4
Reflection shell
Resolution (Å)Redundancy (%)Num. unique allΧ2Diffraction-ID% possible allRmerge(I) obs
3-3.117.220570.8681100
3.11-3.237.320200.8711000.713
3.23-3.387.320430.89211000.52
3.38-3.567.320480.92311000.388
3.56-3.787.320471.17411000.277
3.78-4.077.320680.96811000.223
4.07-4.487.220631.40111000.195
4.48-5.137.220820.9811000.137
5.13-6.467.121180.88111000.152
6.46-506.722150.935199.10.076

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
REFMAC5.2.0019refinement
PDB_EXTRACT3.1data extraction
CrystalCleardata collection
HKL-2000data reduction
HKL-2000data scaling
EPMRphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3→34.06 Å / Cor.coef. Fo:Fc: 0.896 / Cor.coef. Fo:Fc free: 0.852 / Occupancy max: 1 / Occupancy min: 1 / SU B: 23.484 / SU ML: 0.426 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.546 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.3133 1064 5.1 %RANDOM
Rwork0.2523 ---
obs0.2555 20703 99.42 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 294.29 Å2 / Biso mean: 31.7743 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1-5.07 Å20 Å20 Å2
2---2.3 Å20 Å2
3----2.77 Å2
Refinement stepCycle: LAST / Resolution: 3→34.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6077 0 96 188 6361
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0226341
X-RAY DIFFRACTIONr_angle_refined_deg1.3091.9628623
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4685772
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.74223.916286
X-RAY DIFFRACTIONr_dihedral_angle_3_deg21.10215997
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.2751534
X-RAY DIFFRACTIONr_chiral_restr0.0890.2946
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.024870
X-RAY DIFFRACTIONr_nbd_refined0.2240.23036
X-RAY DIFFRACTIONr_nbtor_refined0.3170.24217
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1570.2310
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2310.242
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2420.26
X-RAY DIFFRACTIONr_mcbond_it0.2011.53859
X-RAY DIFFRACTIONr_mcangle_it0.41326206
X-RAY DIFFRACTIONr_scbond_it0.72532788
X-RAY DIFFRACTIONr_scangle_it1.2684.52417
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: A / Refine-ID: X-RAY DIFFRACTION

Ens-IDNumberTypeRms dev position (Å)Weight position
11548TIGHT POSITIONAL0.050.05
11489MEDIUM POSITIONAL0.150.5
11548TIGHT THERMAL0.040.5
11489MEDIUM THERMAL0.272
294TIGHT POSITIONAL0.05
294TIGHT THERMAL0.5
LS refinement shellResolution: 3.004→3.082 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.39 72 -
Rwork0.343 1355 -
all-1427 -
obs--95.32 %

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