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- PDB-7d5u: BACE2 xaperone complex with N-{3-[(9S)-7-amino-2,2-difluoro-9-(pr... -

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Basic information

Entry
Database: PDB / ID: 7d5u
TitleBACE2 xaperone complex with N-{3-[(9S)-7-amino-2,2-difluoro-9-(prop-1-yn-1-yl)-6-oxa-8-azaspiro[3.5]non-7-en-9-yl]-4-fluorophenyl}-5-cyanopyridine-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. / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily
Similarity search - Domain/homology
Chem-GX6 / Beta-secretase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.04 Å
AuthorsFujimoto, K. / Yoshida, S. / Tadano, G. / Asada, N. / Fuchino, K. / Suzuki, S. / Matsuoka, E. / Yamamoto, T. / Yamamoto, S. / Ando, S. ...Fujimoto, K. / Yoshida, S. / Tadano, G. / Asada, N. / Fuchino, K. / Suzuki, S. / Matsuoka, E. / Yamamoto, T. / Yamamoto, S. / Ando, S. / Kanegawa, N. / Tonomura, Y. / Ito, H. / Moechars, D. / Rombouts, F.J.R. / Gijsen, H.J.M. / Kusakabe, K.I.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Structure-Based Approaches to Improving Selectivity through Utilizing Explicit Water Molecules: Discovery of Selective beta-Secretase (BACE1) Inhibitors over BACE2.
Authors: Fujimoto, K. / Yoshida, S. / Tadano, G. / Asada, N. / Fuchino, K. / Suzuki, S. / Matsuoka, E. / Yamamoto, T. / Yamamoto, S. / Ando, S. / Kanegawa, N. / Tonomura, Y. / Ito, H. / Moechars, D. ...Authors: Fujimoto, K. / Yoshida, S. / Tadano, G. / Asada, N. / Fuchino, K. / Suzuki, S. / Matsuoka, E. / Yamamoto, T. / Yamamoto, S. / Ando, S. / Kanegawa, N. / Tonomura, Y. / Ito, H. / Moechars, D. / Rombouts, F.J.R. / Gijsen, H.J.M. / Kusakabe, K.I.
History
DepositionSep 28, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 31, 2021Provider: repository / Type: Initial release
Revision 1.1Apr 7, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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)54,6653
Polymers54,2122
Non-polymers4531
Water2,378132
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: assay for oligomerization
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1690 Å2
ΔGint-7 kcal/mol
Surface area19370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.926, 74.339, 108.389
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: 12106.443 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-GX6 / N-[3-[(9S)-7-azanyl-2,2-bis(fluoranyl)-9-prop-1-ynyl-6-oxa-8-azaspiro[3.5]non-7-en-9-yl]-4-fluoranyl-phenyl]-5-cyano-pyridine-2-carboxamide


Mass: 453.417 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H18F3N5O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 132 / 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: 2.27 Å3/Da / Density % sol: 45.78 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 293K

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.999999701977 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 18, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999999701977 Å / Relative weight: 1
ReflectionResolution: 2.04→61.31 Å / Num. obs: 31792 / % possible obs: 96 % / Redundancy: 4.333 % / Biso Wilson estimate: 50.939 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.039 / Rrim(I) all: 0.045 / Χ2: 1.088 / Net I/σ(I): 18.57 / Num. measured all: 137754 / Scaling rejects: 66
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
2.04-2.293.6890.4893.0530870954583680.910.5787.7
2.29-2.534.7170.2497.2227880591859100.9730.28399.9
2.53-2.94.6010.11514.0326935587258540.9920.13199.7
2.9-3.544.6360.04526.2223914518351580.9980.05299.5
3.54-4.484.2980.02740.1913942327132440.9990.03199.2
4.48-5.764.5120.02250.017643171416940.9990.02598.8
5.76-8.44.2210.01953.414381105610380.9990.02298.3
8.4-13.444.2540.01566.64165940239010.01797
13.44-61.313.8970.01861.455301471360.9980.02192.5

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
XSCALEdata scaling
PDB_EXTRACT3.25data extraction
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: not available

Resolution: 2.04→61.31 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.942 / SU R Cruickshank DPI: 0.195 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.222 / ESU R Free: 0.191 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2538 1745 5.5 %RANDOM
Rwork0.2072 ---
obs0.2097 30047 96.03 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 229.66 Å2 / Biso mean: 68.533 Å2 / Biso min: 39.33 Å2
Baniso -1Baniso -2Baniso -3
1-0.44 Å2-0 Å2-0 Å2
2---4.14 Å20 Å2
3---3.69 Å2
Refinement stepCycle: final / Resolution: 2.04→61.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3625 0 33 132 3790
Biso mean--61 66.02 -
Num. residues----484
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0460.023777
X-RAY DIFFRACTIONr_bond_other_d00.023327
X-RAY DIFFRACTIONr_angle_refined_deg3.5061.9585154
X-RAY DIFFRACTIONr_angle_other_deg4.33737698
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.4735486
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.84924.082147
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.52615554
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.7841515
X-RAY DIFFRACTIONr_chiral_restr0.2350.2578
X-RAY DIFFRACTIONr_gen_planes_refined0.0230.0214256
X-RAY DIFFRACTIONr_gen_planes_other0.050.02798
LS refinement shellResolution: 2.04→2.093 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.343 105 -
Rwork0.343 1777 -
all-1882 -
obs--77.19 %

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