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- PDB-7f1g: BACE2 xaperone complex with N-{3-[(4R,5R,6R)-2-amino-5-fluoro-4,6... -

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Basic information

Entry
Database: PDB / ID: 7f1g
TitleBACE2 xaperone complex with N-{3-[(4R,5R,6R)-2-amino-5-fluoro-4,6-dimethyl-5,6-dihydro-4H-1,3-thiazin-4-yl]-4-fluorophenyl}-2H,3H-[1,4]dioxino[2,3-c]pyridine-7-carboxamide
Components
  • Beta-secretase 2
  • XAPERONE
KeywordsHYDROLASE / Beta-secretase 2
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. / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily
Similarity search - Domain/homology
Chem-0QQ / Beta-secretase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsUeno, T. / Matsuoka, E. / Asada, N. / Yamamoto, S. / Kanegawa, N. / Ito, M. / Ito, H. / Moechars, D. / Rombouts, F.J.R. / Gijsen, H.J.M. / Kusakabe, K.I.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Discovery of Extremely Selective Fused Pyridine-Derived beta-Site Amyloid Precursor Protein-Cleaving Enzyme (BACE1) Inhibitors with High In Vivo Efficacy through 10s Loop Interactions.
Authors: Ueno, T. / Matsuoka, E. / Asada, N. / Yamamoto, S. / Kanegawa, N. / Ito, M. / Ito, H. / Moechars, D. / Rombouts, F.J.R. / Gijsen, H.J.M. / Kusakabe, K.I.
History
DepositionJun 9, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 23, 2022Provider: repository / Type: Initial release

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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)54,5083
Polymers54,0742
Non-polymers4341
Water5,495305
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1710 Å2
ΔGint-6 kcal/mol
Surface area19820 Å2
Unit cell
Length a, b, c (Å)63.438, 74.635, 106.763
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
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: 11968.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#3: Chemical ChemComp-0QQ / N-[3-[(4R,5R,6R)-2-azanyl-5-fluoranyl-4,6-dimethyl-5,6-dihydro-1,3-thiazin-4-yl]-4-fluoranyl-phenyl]-2,3-dihydro-[1,4]dioxino[2,3-c]pyridine-7-carboxamide


Mass: 434.460 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H20F2N4O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 305 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.26 Å3/Da / Density % sol: 45.5 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: not available

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.99987 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 25, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99987 Å / Relative weight: 1
ReflectionResolution: 1.5→61.17 Å / Num. obs: 77803 / % possible obs: 95.1 % / Redundancy: 2.9 % / Rmerge(I) obs: 0.037 / Net I/σ(I): 14.61
Reflection shellResolution: 1.5→1.75 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.48 / Num. unique obs: 29017 / % possible all: 96.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
XSCALEdata scaling
PDB_EXTRACT3.27data extraction
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 1.5→61.17 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.952 / SU B: 2.837 / SU ML: 0.093 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.092 / ESU R Free: 0.088 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2446 4374 5.6 %RANDOM
Rwork0.2255 ---
obs0.2266 73429 95.11 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 74.09 Å2 / Biso mean: 27.607 Å2 / Biso min: 10.7 Å2
Baniso -1Baniso -2Baniso -3
1--0.84 Å20 Å20 Å2
2---1.71 Å20 Å2
3---2.55 Å2
Refinement stepCycle: final / Resolution: 1.5→61.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3588 0 50 305 3943
Biso mean--29.74 34.61 -
Num. residues----475
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.023730
X-RAY DIFFRACTIONr_bond_other_d0.0030.023434
X-RAY DIFFRACTIONr_angle_refined_deg1.4581.9575080
X-RAY DIFFRACTIONr_angle_other_deg1.21137876
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9445476
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.8923.605147
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.25315560
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.8741519
X-RAY DIFFRACTIONr_chiral_restr0.080.2572
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0214247
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02872
LS refinement shellResolution: 1.5→1.539 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.397 325 -
Rwork0.401 5491 -
all-5816 -
obs--96.97 %

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