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- PDB-5t1w: Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging G... -

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Basic information

Entry
Database: PDB / ID: 5t1w
TitleAminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE inhibitor / beta secretase / alzheimer's / inhibitor / 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-74B / IODIDE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Resolution: 2.96 Å
AuthorsParris, K.D. / Vajdos, F.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality.
Authors: Butler, C.R. / Ogilvie, K. / Martinez-Alsina, L. / Barreiro, G. / Beck, E.M. / Nolan, C.E. / Atchison, K. / Benvenuti, E. / Buzon, L. / Doran, S. / Gonzales, C. / Helal, C.J. / Hou, X. / ...Authors: Butler, C.R. / Ogilvie, K. / Martinez-Alsina, L. / Barreiro, G. / Beck, E.M. / Nolan, C.E. / Atchison, K. / Benvenuti, E. / Buzon, L. / Doran, S. / Gonzales, C. / Helal, C.J. / Hou, X. / Hsu, M.H. / Johnson, E.F. / Lapham, K. / Lanyon, L. / Parris, K. / O'Neill, B.T. / Riddell, D. / Robshaw, A. / Vajdos, F. / Brodney, M.A.
History
DepositionAug 22, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 11, 2017Provider: repository / Type: Initial release
Revision 1.1Jan 25, 2017Group: 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)47,72013
Polymers46,4411
Non-polymers1,27912
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)101.460, 101.460, 170.660
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: 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 , 6 types, 12 molecules

#2: Chemical ChemComp-74B / (4aR,6R,8aS)-8a-(2,4-difluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine


Mass: 427.408 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H19F6N3OS
#3: Chemical ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 3 / 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.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#7: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl

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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: 2.73 Å3/Da / Density % sol: 54.95 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 20-22.5% (w/v) PEG 5000 monomethylethyl (MME), 200 mM sodium citrate (pH 6.6), 200 mM ammonium iodide

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Oct 20, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5 Å / Relative weight: 1
ReflectionResolution: 2.962→170.66 Å / Num. obs: 11450 / % possible obs: 100 % / Redundancy: 17.1 % / Biso Wilson estimate: 48.64 Å2 / Rmerge(I) obs: 0.244 / Rpim(I) all: 0.06 / Rrim(I) all: 0.252 / Net I/σ(I): 14.2 / Num. measured all: 195672
Reflection shell

Diffraction-ID: 1 / Rejects: _ / % possible all: 100

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique allRpim(I) allRrim(I) allNet I/σ(I) obs
2.962-2.97217.80.66620471150.1610.6865.3
13.746-170.6610.60.07417211630.0210.07725.3

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Processing

Software
NameVersionClassification
SCALAdata scaling
BUSTER-TNT2.11.2refinement
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
RefinementResolution: 2.96→32.65 Å / Cor.coef. Fo:Fc: 0.9168 / Cor.coef. Fo:Fc free: 0.8252 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.377
RfactorNum. reflection% reflectionSelection details
Rfree0.2499 543 4.77 %RANDOM
Rwork0.1782 ---
obs0.1816 11383 99.75 %-
Displacement parametersBiso max: 86.86 Å2 / Biso mean: 16.88 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1--0.6049 Å20 Å20 Å2
2---0.6049 Å20 Å2
3---1.2099 Å2
Refine analyzeLuzzati coordinate error obs: 0.339 Å
Refinement stepCycle: final / Resolution: 2.96→32.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2909 0 57 0 2966
Biso mean--26.33 --
Num. residues----371
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1017SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes66HARMONIC2
X-RAY DIFFRACTIONt_gen_planes452HARMONIC5
X-RAY DIFFRACTIONt_it3042HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion387SEMIHARMONIC5
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_contact3469SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3042HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg4135HARMONIC21.21
X-RAY DIFFRACTIONt_omega_torsion3.28
X-RAY DIFFRACTIONt_other_torsion18.62
LS refinement shellResolution: 2.96→3.24 Å / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.2875 132 5.03 %
Rwork0.1981 2493 -
all0.2027 2625 -
obs--99.75 %

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