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- PDB-4wy1: Crystal structure of human BACE-1 bound to Compound 24B -

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Basic information

Entry
Database: PDB / ID: 4wy1
TitleCrystal structure of human BACE-1 bound to Compound 24B
ComponentsBeta-secretase 1
KeywordsHydrolase/hydrolase inhibitor / Beta secretase BACE 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 / 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 / recycling endosome / protein processing / 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 / 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-3VO / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Resolution: 1.98 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 14, 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 / Structure summary
Category: citation / entity_src_gen ...citation / entity_src_gen / pdbx_struct_assembly / pdbx_struct_assembly_prop / pdbx_struct_oper_list / software / struct_keywords
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_assembly.oligomeric_details / _pdbx_struct_assembly_prop.type / _pdbx_struct_assembly_prop.value / _pdbx_struct_oper_list.symmetry_operation / _software.classification / _struct_keywords.text

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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)45,4412
Polymers45,1571
Non-polymers2841
Water6,846380
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area17520 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.856, 103.719, 100.579
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 / 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: 45156.730 Da / Num. of mol.: 1 / Fragment: protease (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) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-3VO / (4aR,8aS)-8a-(2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine


Mass: 284.325 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H14F2N2OS
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 380 / 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: 2.16 Å3/Da / Density % sol: 43.1 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop
Details: 30% PEG 200;0.1 M sodium acetate, pH 5.2-5.4; protein buffer is NaBorate, pH 8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Apr 7, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.976→100.579 Å / Num. all: 27776 / Num. obs: 27776 / % possible obs: 99.9 % / Redundancy: 4.7 % / Biso Wilson estimate: 26.75 Å2 / Rpim(I) all: 0.035 / Rrim(I) all: 0.076 / Rsym value: 0.058 / Net I/av σ(I): 12.978 / Net I/σ(I): 19.3 / Num. measured all: 130873
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRsym valueNet I/σ(I) obs% possible all
1.976-2.084.50.4121.91806040140.2510.4123.399.9
2.08-2.214.70.2812.81781937960.1680.2814.899.9
2.21-2.364.70.2043.81681935680.1210.2046.6100
2.36-2.554.80.1574.91577233140.0920.1578.5100
2.55-2.84.80.1077.21477430810.0620.10712100
2.8-3.124.80.06611.81339527860.0380.06618.4100
3.12-3.614.80.03620.91201224860.0210.03631.5100
3.61-4.424.80.02234.11011321130.0130.02253.5100
4.42-6.254.70.01740.3786416580.0110.01762.399.8
6.25-100.5794.40.01443.642459600.0110.01472.699.4

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Processing

Software
NameVersionClassification
SCALA3.3.16data scaling
BUSTER-TNTBUSTER 2.11.1refinement
PDB_EXTRACT3.15data extraction
RefinementResolution: 1.98→37.43 Å / Cor.coef. Fo:Fc: 0.9442 / Cor.coef. Fo:Fc free: 0.9139 / SU R Cruickshank DPI: 0.168 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.184 / SU Rfree Blow DPI: 0.16 / SU Rfree Cruickshank DPI: 0.155
RfactorNum. reflection% reflectionSelection details
Rfree0.2199 1451 5.26 %RANDOM
Rwork0.1672 ---
obs0.1699 27587 99.88 %-
Displacement parametersBiso max: 176.14 Å2 / Biso mean: 35.93 Å2 / Biso min: 11.76 Å2
Baniso -1Baniso -2Baniso -3
1-2.1016 Å20 Å20 Å2
2--7.8424 Å20 Å2
3----9.944 Å2
Refine analyzeLuzzati coordinate error obs: 0.196 Å
Refinement stepCycle: final / Resolution: 1.98→37.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3106 0 19 380 3505
Biso mean--22.39 46.55 -
Num. residues----394
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1078SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes75HARMONIC2
X-RAY DIFFRACTIONt_gen_planes468HARMONIC5
X-RAY DIFFRACTIONt_it3210HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion412SEMIHARMONIC5
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_contact4037SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3210HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg4368HARMONIC21.11
X-RAY DIFFRACTIONt_omega_torsion3.79
X-RAY DIFFRACTIONt_other_torsion17.2
LS refinement shellResolution: 1.98→2.06 Å / Total num. of bins used: 14
RfactorNum. reflection% reflection
Rfree0.2355 153 5.35 %
Rwork0.2014 2708 -
all0.2033 2861 -
obs--99.88 %

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