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- PDB-4wy6: Crystal structure of human BACE-1 bound to Compound 36 -

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Basic information

Entry
Database: PDB / ID: 4wy6
TitleCrystal structure of human BACE-1 bound to Compound 36
ComponentsBeta-secretase 1
KeywordsHydrolase/hydrolase inhibitor / BACE 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-3VP / IODIDE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.1 Å
AuthorsVajdos, F.F.
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 15, 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

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Assembly

Deposited unit
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,70411
Polymers46,4411
Non-polymers1,26310
Water5,657314
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1770 Å2
ΔGint10 kcal/mol
Surface area15750 Å2
MethodPISA
Unit cell
Length a, b, c (Å)102.871, 102.871, 170.884
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122
Components on special symmetry positions
IDModelComponents
11A-546-

HOH

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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: 46440.980 Da / Num. of mol.: 1 / Fragment: protease (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
#2: Chemical ChemComp-3VP / (4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine


Mass: 316.342 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H15F3N2OS
#3: Chemical
ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: I
#4: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 314 / 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: 2.81 Å3/Da / Density % sol: 56.23 %
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: Jul 16, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→89.09 Å / Num. obs: 31982 / % possible obs: 100 % / Redundancy: 18.2 % / Biso Wilson estimate: 44.76 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.139 / Rpim(I) all: 0.034 / Net I/σ(I): 15.5 / Num. measured all: 581013
Reflection shellResolution: 2.1→2.42 Å / Redundancy: 18.8 % / Rmerge(I) obs: 0.901 / Mean I/σ(I) obs: 3.4 / Num. measured all: 206184 / Num. unique all: 10947 / CC1/2: 0.875 / Rpim(I) all: 0.215 / Rejects: 0 / % possible all: 100

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Processing

Software
NameVersionClassification
Aimless0.3.5data scaling
BUSTER-TNTBUSTER 2.11.5refinement
PDB_EXTRACT3.15data extraction
RefinementResolution: 2.1→27.41 Å / Cor.coef. Fo:Fc: 0.9483 / Cor.coef. Fo:Fc free: 0.9442 / SU R Cruickshank DPI: 0.163 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.177 / SU Rfree Blow DPI: 0.141 / SU Rfree Cruickshank DPI: 0.135
RfactorNum. reflection% reflectionSelection details
Rfree0.2009 1641 5.15 %RANDOM
Rwork0.1849 ---
obs0.1858 31871 100 %-
Displacement parametersBiso max: 149.69 Å2 / Biso mean: 42.4 Å2 / Biso min: 22.71 Å2
Baniso -1Baniso -2Baniso -3
1-0.3706 Å20 Å20 Å2
2--0.3706 Å20 Å2
3----0.7412 Å2
Refine analyzeLuzzati coordinate error obs: 0.229 Å
Refinement stepCycle: final / Resolution: 2.1→27.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2932 0 66 314 3312
Biso mean--75.31 51.27 -
Num. residues----373
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1031SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes68HARMONIC2
X-RAY DIFFRACTIONt_gen_planes460HARMONIC5
X-RAY DIFFRACTIONt_it3099HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion391SEMIHARMONIC5
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_contact3461SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3099HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg4244HARMONIC21.06
X-RAY DIFFRACTIONt_omega_torsion3.65
X-RAY DIFFRACTIONt_other_torsion16.5
LS refinement shellResolution: 2.1→2.17 Å / Total num. of bins used: 16
RfactorNum. reflection% reflection
Rfree0.254 145 5.07 %
Rwork0.2217 2713 -
all0.2233 2858 -
obs--100 %

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