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- PDB-6jsf: Crystal Structure of BACE1 in complex with N-(3-((4S,5S)-2-amino-... -

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Basic information

Entry
Database: PDB / ID: 6jsf
TitleCrystal Structure of BACE1 in complex with N-(3-((4S,5S)-2-amino-4-methyl-5-phenyl-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-(fluoromethoxy)pyrazine-2-carboxamide
ComponentsBeta-secretase 1
KeywordsHYDROLASE / GS-hBACE1(43-454)
Function / homology
Function and homology information


memapsin 2 / Golgi-associated vesicle lumen / beta-aspartyl-peptidase activity / signaling receptor ligand precursor processing / amyloid-beta formation / amyloid precursor protein catabolic process / membrane protein ectodomain proteolysis / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / prepulse inhibition ...memapsin 2 / Golgi-associated vesicle lumen / beta-aspartyl-peptidase activity / signaling receptor ligand precursor processing / amyloid-beta formation / amyloid precursor protein catabolic process / membrane protein ectodomain proteolysis / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / prepulse inhibition / cellular response to manganese ion / multivesicular body / presynaptic modulation of chemical synaptic transmission / protein serine/threonine kinase binding / cellular response to copper ion / hippocampal mossy fiber to CA3 synapse / trans-Golgi network / recycling endosome / protein processing / response to lead ion / cellular response to amyloid-beta / synaptic vesicle / late endosome / peptidase activity / positive regulation of neuron apoptotic process / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / aspartic-type endopeptidase activity / early endosome / lysosome / endosome membrane / endosome / membrane raft / endoplasmic reticulum lumen / Amyloid fiber formation / axon / neuronal cell body / dendrite / enzyme binding / cell surface / Golgi apparatus / 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-C7X / IODIDE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsFujimoto, K. / Matsuoka, E. / Asada, N. / Tadano, G. / Yamamoto, T. / Nakahara, K. / Fuchino, K. / Ito, H. / Kanegawa, N. / Moechars, D. ...Fujimoto, K. / Matsuoka, E. / Asada, N. / Tadano, G. / Yamamoto, T. / Nakahara, K. / Fuchino, K. / Ito, H. / Kanegawa, N. / Moechars, D. / Gijsen, H.J.M. / Kusakabe, K.I.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Structure-Based Design of Selective beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors: Targeting the Flap to Gain Selectivity over BACE2.
Authors: Fujimoto, K. / Matsuoka, E. / Asada, N. / Tadano, G. / Yamamoto, T. / Nakahara, K. / Fuchino, K. / Ito, H. / Kanegawa, N. / Moechars, D. / Gijsen, H.J.M. / Kusakabe, K.I.
History
DepositionApr 8, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 28, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 22, 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
Revision 1.2Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)47,90711
Polymers46,3931
Non-polymers1,51410
Water2,774154
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: fluorescence resonance energy transfer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area90 Å2
ΔGint-1 kcal/mol
Surface area15850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)102.535, 102.535, 170.350
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-506-

IOD

21A-627-

HOH

31A-738-

HOH

41A-752-

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: 46393.043 Da / Num. of mol.: 1
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-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: I
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-C7X / N-[3-[(4S,5S)-2-azanyl-4-methyl-5-phenyl-5,6-dihydro-1,3-thiazin-4-yl]-4-fluoranyl-phenyl]-5-(fluoranylmethoxy)pyrazine-2-carboxamide


Mass: 469.507 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H21F2N5O2S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 154 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.79 Å3/Da / Density % sol: 60.28 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.2 M sodium citrate, 0.2 M ammonium iodide, 18.4%(w/v) polyethylene glycol 5000 monomethyl ether, pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54178 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Sep 8, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. obs: 24210 / % possible obs: 99.6 % / Redundancy: 9.7 % / Rmerge(I) obs: 0.13 / Net I/σ(I): 20.9
Reflection shellResolution: 2.3→2.34 Å / Rmerge(I) obs: 0.417 / Num. unique obs: 1198

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1W50

1w50


Resolution: 2.3→20 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.937 / SU B: 5.341 / SU ML: 0.127 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.254 / ESU R Free: 0.193
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2127 2454 10.2 %RANDOM
Rwork0.1831 ---
obs0.1861 21680 99.58 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 107.61 Å2 / Biso mean: 39.439 Å2 / Biso min: 24.01 Å2
Baniso -1Baniso -2Baniso -3
1-0.27 Å20.13 Å20 Å2
2--0.27 Å20 Å2
3----0.86 Å2
Refinement stepCycle: final / Resolution: 2.3→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2917 0 48 154 3119
Biso mean--47.64 39.61 -
Num. residues----374
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0193036
X-RAY DIFFRACTIONr_angle_refined_deg1.2911.9554126
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4095371
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.60823.433134
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.04215465
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.0241518
X-RAY DIFFRACTIONr_chiral_restr0.0810.2449
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212319
LS refinement shellResolution: 2.3→2.359 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.27 185 -
Rwork0.223 1529 -
all-1714 -
obs--99.54 %

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