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- PDB-5t1u: Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging G... -

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Basic information

Entry
Database: PDB / ID: 5t1u
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 / detection of mechanical stimulus involved in sensory perception of pain / amyloid-beta metabolic process / cellular response to manganese ion ...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 / detection of mechanical stimulus involved in sensory perception of pain / amyloid-beta metabolic process / cellular response to manganese ion / prepulse inhibition / protein serine/threonine kinase binding / cellular response to copper ion / presynaptic modulation of chemical synaptic transmission / multivesicular body / hippocampal mossy fiber to CA3 synapse / response to lead ion / trans-Golgi network / recycling endosome / protein processing / positive regulation of neuron apoptotic process / cellular response to amyloid-beta / late endosome / synaptic vesicle / 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
IODIDE ION / Chem-P6U / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.78 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
Revision 1.2Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)47,3257
Polymers46,4411
Non-polymers8846
Water5,080282
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)102.497, 102.497, 171.693
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122
Components on special symmetry positions
IDModelComponents
11A-727-

HOH

21A-765-

HOH

31A-766-

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: 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-P6U / (4S)-4-[2,4-difluoro-5-({[1-(trifluoromethyl)cyclopropyl]amino}methyl)phenyl]-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-amine


Mass: 379.391 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H18F5N3S
#3: Chemical ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: I
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 282 / 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: 56.12 %
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: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1.5 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 11, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5 Å / Relative weight: 1
ReflectionResolution: 1.78→88.77 Å / Num. obs: 52069 / % possible obs: 100 % / Redundancy: 19.3 % / Biso Wilson estimate: 31.99 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 29.8
Reflection shellResolution: 1.78→1.99 Å / Redundancy: 19.5 % / Rmerge(I) obs: 0.901 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIXDEV_1999refinement
Aimless0.3.5data scaling
PDB_EXTRACT3.2data extraction
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 1W50

1w50


Resolution: 1.78→44.38 Å / SU ML: 0.19 / Cross valid method: THROUGHOUT / σ(F): 1.91 / Phase error: 20.39 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.206 2624 5.05 %RANDOM
Rwork0.187 ---
obs0.188 51983 100 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 35.92 Å2
Refinement stepCycle: LAST / Resolution: 1.78→44.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2975 0 36 282 3293
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0183102
X-RAY DIFFRACTIONf_angle_d1.5994226
X-RAY DIFFRACTIONf_dihedral_angle_d14.1361125
X-RAY DIFFRACTIONf_chiral_restr0.098461
X-RAY DIFFRACTIONf_plane_restr0.008552
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7763-1.80860.31051240.28752554X-RAY DIFFRACTION100
1.8086-1.84340.25461180.2542571X-RAY DIFFRACTION100
1.8434-1.8810.281500.23662503X-RAY DIFFRACTION100
1.881-1.92190.30231160.22982600X-RAY DIFFRACTION100
1.9219-1.96660.26291380.21782555X-RAY DIFFRACTION100
1.9666-2.01580.24951420.21192533X-RAY DIFFRACTION100
2.0158-2.07030.23641380.20192565X-RAY DIFFRACTION100
2.0703-2.13120.22591280.19772570X-RAY DIFFRACTION100
2.1312-2.20.22931290.19842569X-RAY DIFFRACTION100
2.2-2.27860.24751470.19342588X-RAY DIFFRACTION100
2.2786-2.36990.22211420.19782547X-RAY DIFFRACTION100
2.3699-2.47770.19771300.19172592X-RAY DIFFRACTION100
2.4777-2.60830.22671330.18942606X-RAY DIFFRACTION100
2.6083-2.77170.19811480.19122593X-RAY DIFFRACTION100
2.7717-2.98570.23251400.18952598X-RAY DIFFRACTION100
2.9857-3.28610.19781280.17742648X-RAY DIFFRACTION100
3.2861-3.76140.18671820.16592605X-RAY DIFFRACTION100
3.7614-4.73810.15541430.15432693X-RAY DIFFRACTION100
4.7381-44.39630.20631480.1942869X-RAY DIFFRACTION100

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