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- PDB-4x2l: Crystal structure of human BACE-1 bound to Compound 6 -

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Basic information

Entry
Database: PDB / ID: 4x2l
TitleCrystal structure of human BACE-1 bound to Compound 6
ComponentsBeta-secretase 1
KeywordsHydrolase/Hydrolase inhibitor / Beta-secretase / 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 / 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
Chem-3WP / IODIDE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.55 Å
AuthorsVajdos, F.F. / Parris, K.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Discovery of a Series of Efficient, Centrally Efficacious BACE1 Inhibitors through Structure-Based Drug Design.
Authors: Butler, C.R. / Brodney, M.A. / Beck, E.M. / Barreiro, G. / Nolan, C.E. / Pan, F. / Vajdos, F. / Parris, K. / Varghese, A.H. / Helal, C.J. / Lira, R. / Doran, S.D. / Riddell, D.R. / Buzon, L. ...Authors: Butler, C.R. / Brodney, M.A. / Beck, E.M. / Barreiro, G. / Nolan, C.E. / Pan, F. / Vajdos, F. / Parris, K. / Varghese, A.H. / Helal, C.J. / Lira, R. / Doran, S.D. / Riddell, D.R. / Buzon, L.M. / Dutra, J.K. / Martinez-Alsina, L.A. / Ogilvie, K. / Murray, J.C. / Young, J.M. / Atchison, K. / Robshaw, A. / Gonzales, C. / Wang, J. / Zhang, Y. / O'Neill, B.T.
History
DepositionNov 26, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 4, 2015Provider: repository / Type: Initial release
Revision 1.1Apr 8, 2015Group: Database references
Revision 1.2Nov 22, 2017Group: Database references / Derived calculations ...Database references / Derived calculations / Refinement description / Source and taxonomy
Category: citation / entity_src_gen ...citation / entity_src_gen / pdbx_struct_oper_list / software
Item: _citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag ..._citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_oper_list.symmetry_operation / _software.classification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,41611
Polymers46,4411
Non-polymers97510
Water1,65792
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area15620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.420, 103.420, 168.330
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122

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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: protease
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 , 6 types, 102 molecules

#2: Chemical ChemComp-3WP / (4S)-4-(2,4-difluorophenyl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-amine


Mass: 242.288 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H12F2N2S
#3: Chemical ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: I
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 92 / 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: 2.8 Å3/Da / Density % sol: 56.04 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 6.9
Details: 20% PEG5000MME, 200 mM NaI, 200 mM NaCitrate, PH 6.9, BACE (8.3 mg/ml in 20 mM Tris, 250 mM NaCl, pH 7.5)

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 17, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.55→168.327 Å / Num. all: 18008 / Num. obs: 18008 / % possible obs: 100 % / Redundancy: 17.1 % / Biso Wilson estimate: 52.78 Å2 / Rpim(I) all: 0.023 / Rrim(I) all: 0.098 / Rsym value: 0.093 / Net I/av σ(I): 7.688 / Net I/σ(I): 28.5 / Num. measured all: 307377
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRsym valueNet I/σ(I) obs% possible all
2.55-2.6910.30.421.92630625510.1430.424.7100
2.69-2.8515.10.3582.13664224260.0970.3587.4100
2.85-3.0519.60.2642.84480122900.0620.26412.8100
3.05-3.318.90.1724.34063321460.0410.17219.4100
3.3-3.6119.20.1116.63801419770.0260.11129.3100
3.61-4.0419.60.0739.93536318060.0170.07344.1100
4.04-4.6618.10.05812.32930416190.0140.05853.5100
4.66-5.7118.20.0513.92534513950.0120.0555.9100
5.71-8.0718.30.04615.42027011080.0110.04656.6100
8.07-168.32715.50.03219106996900.0090.03267.999.9

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Processing

Software
NameVersionClassification
SCALA3.3.16data scaling
BUSTER-TNTBUSTER 2.11.5refinement
PDB_EXTRACT3.15data extraction
RefinementResolution: 2.55→89.57 Å / Cor.coef. Fo:Fc: 0.9351 / Cor.coef. Fo:Fc free: 0.908 / SU R Cruickshank DPI: 0.35 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.376 / SU Rfree Blow DPI: 0.253 / SU Rfree Cruickshank DPI: 0.25
RfactorNum. reflection% reflectionSelection details
Rfree0.2385 917 5.11 %RANDOM
Rwork0.1884 ---
obs0.191 17954 99.59 %-
Displacement parametersBiso max: 175.44 Å2 / Biso mean: 41.78 Å2 / Biso min: 15.46 Å2
Baniso -1Baniso -2Baniso -3
1-0.9457 Å20 Å20 Å2
2--0.9457 Å20 Å2
3----1.8914 Å2
Refine analyzeLuzzati coordinate error obs: 0.281 Å
Refinement stepCycle: final / Resolution: 2.55→89.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2909 0 58 92 3059
Biso mean--55.25 38.07 -
Num. residues----371
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1009SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes66HARMONIC2
X-RAY DIFFRACTIONt_gen_planes456HARMONIC5
X-RAY DIFFRACTIONt_it3044HARMONIC20
X-RAY DIFFRACTIONt_nbd2SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion385SEMIHARMONIC5
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_contact3425SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3044HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg4143HARMONIC21.12
X-RAY DIFFRACTIONt_omega_torsion3.5
X-RAY DIFFRACTIONt_other_torsion18.03
LS refinement shellResolution: 2.55→2.71 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.2453 150 5.41 %
Rwork0.2089 2622 -
all0.211 2772 -
obs--99.59 %

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