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- PDB-4xxs: Crystal structure of BACE1 with a pyrazole-substituted tetrahydro... -

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Basic information

Entry
Database: PDB / ID: 4xxs
TitleCrystal structure of BACE1 with a pyrazole-substituted tetrahydropyran thioamidine
ComponentsBeta-secretase 1
Keywordshydrolase/hydrolase inhibitor / Amyloid Precursor Protein Secretases / Aspartic Acid Endopeptidases / Drug Design / Structure-Activity Relationship / 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 / hippocampal mossy fiber to CA3 synapse / 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 / peptidase activity / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / aspartic-type endopeptidase activity / lysosome / 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
IODIDE ION / Chem-SI5 / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.86 Å
AuthorsParris, K.D. / Pandit, J.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Utilizing Structures of CYP2D6 and BACE1 Complexes To Reduce Risk of Drug-Drug Interactions with a Novel Series of Centrally Efficacious BACE1 Inhibitors.
Authors: Brodney, M.A. / Beck, E.M. / Butler, C.R. / Barreiro, G. / Johnson, E.F. / Riddell, D. / Parris, K. / Nolan, C.E. / Fan, Y. / Atchison, K. / Gonzales, C. / Robshaw, A.E. / Doran, S.D. / ...Authors: Brodney, M.A. / Beck, E.M. / Butler, C.R. / Barreiro, G. / Johnson, E.F. / Riddell, D. / Parris, K. / Nolan, C.E. / Fan, Y. / Atchison, K. / Gonzales, C. / Robshaw, A.E. / Doran, S.D. / Bundesmann, M.W. / Buzon, L. / Dutra, J. / Henegar, K. / LaChapelle, E. / Hou, X. / Rogers, B.N. / Pandit, J. / Lira, R. / Martinez-Alsina, L. / Mikochik, P. / Murray, J.C. / Ogilvie, K. / Price, L. / Sakya, S.M. / Yu, A. / Zhang, Y. / O'Neill, B.T.
History
DepositionJan 30, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 1, 2015Provider: repository / Type: Initial release
Revision 1.1Apr 8, 2015Group: Database references
Revision 1.2Apr 22, 2015Group: 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)47,4789
Polymers46,4411
Non-polymers1,0378
Water5,386299
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)102.350, 102.350, 170.550
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122
Detailsbiological unit is the same as asym.

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Beta-secretase 1 / Aspartyl protease 2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta-site APP ...Aspartyl protease 2 / 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

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Non-polymers , 5 types, 307 molecules

#2: Chemical ChemComp-SI5 / (4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine


Mass: 364.413 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H18F2N4OS
#3: Chemical ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: I
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 299 / 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: 2.78 Å3/Da / Density % sol: 55.7 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6.6
Details: BACE1 lacking the pro-segment was concentrated to ~14 mg/mL in 20 mM Tris pH 7.4 and 250 mM NaCl. Crystallization was carried out by the vapor diffusion method against 200 mM sodium citrate ...Details: BACE1 lacking the pro-segment was concentrated to ~14 mg/mL in 20 mM Tris pH 7.4 and 250 mM NaCl. Crystallization was carried out by the vapor diffusion method against 200 mM sodium citrate tribasic dihydrate, 22% PEG 5K monomethyl ether and 200 mM ammonium iodide.

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Data collection

DiffractionMean temperature: 83 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 29, 2012
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.86→50 Å / Num. obs: 44909 / % possible obs: 99.8 % / Redundancy: 17.2 % / Biso Wilson estimate: 44.2 Å2 / Rmerge(I) obs: 0.121 / Χ2: 0.937 / Net I/av σ(I): 29.417 / Net I/σ(I): 4.9 / Num. measured all: 770525
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Num. unique allΧ2% possible allRmerge(I) obs
1.86-1.897.521320.61196.6
1.89-1.9310.221930.60499.8
1.93-1.9612.821900.61999.9
1.96-21522070.64199.9
2-2.0516.322160.6471000.964
2.05-2.0917.822040.6631000.81
2.09-2.1518.221950.681000.667
2.15-2.2119.422090.6981000.542
2.21-2.2719.522280.72499.90.46
2.27-2.3419.122310.7481000.38
2.34-2.4318.922280.7751000.336
2.43-2.5218.222130.8231000.275
2.52-2.6418.422550.8811000.212
2.64-2.7819.622410.9561000.179
2.78-2.9519.422500.9491000.146
2.95-3.1818.622641.0731000.122
3.18-3.518.622791.2341000.108
3.5-4.0119.523041.3341000.1
4.01-5.0518.123461.5771000.102
5.05-5017.325241.80999.80.108

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Processing

Software
NameVersionClassification
HKL-2000data reduction
BUSTER-TNTBUSTER 2.11.2refinement
PDB_EXTRACT3.15data extraction
HKL-2000data scaling
BUSTER-TNTphasing
RefinementResolution: 1.86→27.23 Å / Cor.coef. Fo:Fc: 0.9576 / Cor.coef. Fo:Fc free: 0.9494 / SU R Cruickshank DPI: 0.109 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.115 / SU Rfree Blow DPI: 0.108 / SU Rfree Cruickshank DPI: 0.104
RfactorNum. reflection% reflectionSelection details
Rfree0.2076 2255 5.03 %RANDOM
Rwork0.1818 ---
obs0.1831 44821 99.68 %-
Displacement parametersBiso max: 299.87 Å2 / Biso mean: 50.02 Å2 / Biso min: 31.99 Å2
Baniso -1Baniso -2Baniso -3
1-4.5971 Å20 Å20 Å2
2--4.5971 Å20 Å2
3----9.1941 Å2
Refine analyzeLuzzati coordinate error obs: 0.215 Å
Refinement stepCycle: final / Resolution: 1.86→27.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2941 0 51 299 3291
Biso mean--60.99 63.26 -
Num. residues----376
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1014SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes68HARMONIC2
X-RAY DIFFRACTIONt_gen_planes461HARMONIC5
X-RAY DIFFRACTIONt_it3066HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion392SEMIHARMONIC5
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_contact3748SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3066HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg4169HARMONIC21.08
X-RAY DIFFRACTIONt_omega_torsion4.01
X-RAY DIFFRACTIONt_other_torsion16.47
LS refinement shellResolution: 1.86→1.91 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2539 150 4.81 %
Rwork0.238 2967 -
all0.2388 3117 -
obs--99.68 %

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