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- PDB-6jsz: BACE2 xaperone complex with N-{3-[(5R)-3-amino-5-methyl-9,9-dioxo... -

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Basic information

Entry
Database: PDB / ID: 6jsz
TitleBACE2 xaperone complex with N-{3-[(5R)-3-amino-5-methyl-9,9-dioxo-2,9lambda6-dithia-4-azaspiro[5.5]undec-3-en-5-yl]-4-fluorophenyl}-5-(fluoromethoxy)pyrazine-2-carboxamide
Components
  • Beta-secretase 2
  • XAPERONE
KeywordsHYDROLASE/IMMUNE SYSTEM / BACE2 / HYDROLASE / HYDROLASE-IMMUNE SYSTEM complex
Function / homology
Function and homology information


memapsin 1 / negative regulation of amyloid precursor protein biosynthetic process / melanosome membrane / melanosome organization / peptide hormone processing / membrane protein ectodomain proteolysis / amyloid-beta metabolic process / trans-Golgi network / protein processing / glucose homeostasis ...memapsin 1 / negative regulation of amyloid precursor protein biosynthetic process / melanosome membrane / melanosome organization / peptide hormone processing / membrane protein ectodomain proteolysis / amyloid-beta metabolic process / trans-Golgi network / protein processing / glucose homeostasis / aspartic-type endopeptidase activity / endosome / Golgi apparatus / endoplasmic reticulum / proteolysis / membrane / plasma membrane
Similarity search - Function
Beta-secretase BACE2 / 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 BACE2 / 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-C7O / Beta-secretase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.53 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Beta-secretase 2
D: XAPERONE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,4214
Polymers53,8742
Non-polymers5472
Water5,386299
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: fluorescence resonance energy transfer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1830 Å2
ΔGint-17 kcal/mol
Surface area19350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)63.542, 74.467, 109.135
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Beta-secretase 2 / / Aspartic-like protease 56 kDa / Aspartyl protease 1 / Asp 1 / Beta-site amyloid precursor protein ...Aspartic-like protease 56 kDa / Aspartyl protease 1 / Asp 1 / Beta-site amyloid precursor protein cleaving enzyme 2 / Beta-site APP cleaving enzyme 2 / Down region aspartic protease / DRAP / Memapsin-1 / Membrane-associated aspartic protease 1 / Theta-secretase


Mass: 42105.391 Da / Num. of mol.: 1 / Mutation: AEPLC, ALP56, ASP21
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE2, AEPLC, ALP56, ASP21, CDA13, UNQ418/PRO852 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9Y5Z0, memapsin 1
#2: Protein XAPERONE


Mass: 11769.089 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
#3: Chemical ChemComp-C7O / N-[3-[(5R)-3-azanyl-5-methyl-9,9-bis(oxidanylidene)-2,9$l^{6}-dithia-4-azaspiro[5.5]undec-3-en-5-yl]-4-fluoranyl-phenyl]-5-(fluoranylmethoxy)pyrazine-2-carboxamide


Mass: 511.565 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H23F2N5O4S2
#4: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 299 / 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: 2.31 Å3/Da / Density % sol: 46.76 % / Description: NONE
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 0.1M TRIS pH 8.0, 25% PEG 3350, pH 8.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 1, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.53→61.51 Å / Num. obs: 78375 / % possible obs: 99.5 % / Redundancy: 4.1 % / Rrim(I) all: 0.04 / Rsym value: 0.035 / Net I/σ(I): 19.09
Reflection shellResolution: 1.53→1.78 Å / Redundancy: 4.1 % / Num. unique obs: 28173 / Rrim(I) all: 0.563 / Rsym value: 0.49 / % possible all: 99.1

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Processing

Software
NameVersionClassification
REFMAC5.8.0151refinement
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3ZKG

3zkg


Resolution: 1.53→61.51 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.95 / SU B: 2.251 / SU ML: 0.077 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.091 / ESU R Free: 0.085
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.237 4099 5.2 %RANDOM
Rwork0.2252 ---
obs0.2258 74276 99.67 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 84.57 Å2 / Biso mean: 28.96 Å2 / Biso min: 15.92 Å2
Baniso -1Baniso -2Baniso -3
1--0.45 Å2-0 Å2-0 Å2
2---1.8 Å20 Å2
3---2.25 Å2
Refinement stepCycle: final / Resolution: 1.53→61.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3560 0 35 299 3894
Biso mean--31 36.44 -
Num. residues----474
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.023711
X-RAY DIFFRACTIONr_bond_other_d0.0030.023403
X-RAY DIFFRACTIONr_angle_refined_deg1.4391.9585052
X-RAY DIFFRACTIONr_angle_other_deg1.18737799
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8595475
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.94423.655145
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.0115554
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.3711518
X-RAY DIFFRACTIONr_chiral_restr0.0790.2566
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.024228
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02865
LS refinement shellResolution: 1.531→1.571 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.347 278 -
Rwork0.342 5361 -
all-5639 -
obs--98.48 %

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