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- PDB-4fm8: Crystal Structure of BACE with Compound 12a -

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Basic information

Entry
Database: PDB / ID: 4fm8
TitleCrystal Structure of BACE with Compound 12a
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / aspartyl 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-0UQ / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.9 Å
AuthorsVajdos, F.F. / Varghese, A.H.
Citation
Journal: J.Med.Chem. / Year: 2012
Title: Spirocyclic sulfamides as beta-secretase 1 (BACE-1) inhibitors for the treatment of Alzheimer's disease: utilization of structure based drug design, WaterMap, and CNS penetration studies to ...Title: Spirocyclic sulfamides as beta-secretase 1 (BACE-1) inhibitors for the treatment of Alzheimer's disease: utilization of structure based drug design, WaterMap, and CNS penetration studies to identify centrally efficacious inhibitors.
Authors: Brodney, M.A. / Barreiro, G. / Ogilvie, K. / Hajos-Korcsok, E. / Murray, J. / Vajdos, F. / Ambroise, C. / Christoffersen, C. / Fisher, K. / Lanyon, L. / Liu, J. / Nolan, C.E. / Withka, J.M. ...Authors: Brodney, M.A. / Barreiro, G. / Ogilvie, K. / Hajos-Korcsok, E. / Murray, J. / Vajdos, F. / Ambroise, C. / Christoffersen, C. / Fisher, K. / Lanyon, L. / Liu, J. / Nolan, C.E. / Withka, J.M. / Borzilleri, K.A. / Efremov, I. / Oborski, C.E. / Varghese, A. / O'Neill, B.T.
#1: Journal: Protein Pept.Lett. / Year: 2008
Title: High yield expression of human BACE constructs in Eschericia coli for refolding, purification, and high resolution diffracting crystal forms.
Authors: Tomasselli, A.G. / Paddock, D.J. / Emmons, T.L. / Mildner, A.M. / Leone, J.W. / Lull, J.M. / Cialdella, J.I. / Prince, D.B. / Fischer, H.D. / Heinrikson, R.L. / Benson, T.E.
History
DepositionJun 15, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 3, 2012Provider: repository / Type: Initial release
Revision 1.1Jun 19, 2013Group: Database references

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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)45,7464
Polymers45,1571
Non-polymers5893
Water4,324240
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)74.719, 103.262, 98.619
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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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: 45156.730 Da / Num. of mol.: 1 / Fragment: UNP Residues 58-453
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-0UQ / (5R,7S)-1-(3-fluorophenyl)-3,7-dimethyl-8-[3-(propan-2-yloxy)benzyl]-2-thia-1,3,8-triazaspiro[4.5]decane 2,2-dioxide


Mass: 461.593 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H32FN3O3S
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 240 / 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: 2.11 Å3/Da / Density % sol: 41.6 %
Crystal growTemperature: 298 K / Method: vapor diffusion
Details: 30% PEG 200, 0.1 M sodium acetate, pH 5.2-5.4, protein buffer is NaBorate, pH 8.5, vapor diffusion, temperature 298K

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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: May 28, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.9→31.26 Å / Num. obs: 30046 / % possible obs: 98.8 % / Redundancy: 4.71 % / Rmerge(I) obs: 0.073 / Χ2: 0.97 / Net I/σ(I): 10.6 / Scaling rejects: 1070
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allΧ2% possible all
1.9-1.974.660.3263.81374529281.1897.7
1.97-2.054.670.274.41393129691.1798.7
2.05-2.144.660.2155.11376629401.0598.1
2.14-2.254.680.1915.91406729871.0398.9
2.25-2.394.690.1586.91410429791.0398.9
2.39-2.584.720.1337.71421529900.9599.1
2.58-2.844.750.1059.81444630210.9299.6
2.84-3.254.760.0714.11459930510.8499.8
3.25-4.094.790.04622.61471030590.7899.6
4.09-31.264.720.04423.51498931220.7697.5

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Processing

Software
NameVersionClassificationNB
d*TREK9.6Ldata scaling
d*TREK9.6Ldata reduction
BUSTER-TNTrefinement
PDB_EXTRACT3.11data extraction
BUSTER2.11.2refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.9→16.59 Å / Cor.coef. Fo:Fc: 0.9468 / Cor.coef. Fo:Fc free: 0.9193 / Occupancy max: 1 / Occupancy min: 0.5 / SU R Cruickshank DPI: 0.171 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2516 1566 5.22 %RANDOM
Rwork0.1987 ---
obs0.2014 30002 98.82 %-
Displacement parametersBiso max: 98.09 Å2 / Biso mean: 32.0781 Å2 / Biso min: 16.31 Å2
Baniso -1Baniso -2Baniso -3
1--1.0861 Å20 Å20 Å2
2--2.0233 Å20 Å2
3----0.9371 Å2
Refine analyzeLuzzati coordinate error obs: 0.207 Å
Refinement stepCycle: LAST / Resolution: 1.9→16.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3106 0 37 240 3383
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1072SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes75HARMONIC2
X-RAY DIFFRACTIONt_gen_planes474HARMONIC5
X-RAY DIFFRACTIONt_it3227HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion415SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3860SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3227HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg4392HARMONIC21.11
X-RAY DIFFRACTIONt_omega_torsion3.85
X-RAY DIFFRACTIONt_other_torsion16.17
LS refinement shellResolution: 1.9→1.97 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.262 142 4.93 %
Rwork0.192 2736 -
all0.1955 2878 -
obs--98.82 %

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