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- PDB-7d5b: BACE2 xaperone complex with N-{3-[(5R)-3-amino-2,5-dimethyl-1,1-d... -

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Basic information

Entry
Database: PDB / ID: 7d5b
TitleBACE2 xaperone complex with N-{3-[(5R)-3-amino-2,5-dimethyl-1,1-dioxo-5,6-dihydro-2H-1lambda6,2,4-thiadiazin-5-yl]-4-fluorophenyl}-5-fluoropyridine-2-carboxamide
Components
  • Beta-secretase 2
  • XAPERONE
KeywordsHYDROLASE/IMMUNE SYSTEM / BACE1 / 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-66F / Beta-secretase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.31 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 25, 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
Revision 1.2Oct 9, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_entry_details.has_protein_modification

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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)54,6809
Polymers54,0032
Non-polymers6777
Water9,638535
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: assay for oligomerization
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2590 Å2
ΔGint-34 kcal/mol
Surface area19280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)63.807, 74.396, 110.408
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 2 types, 2 molecules AD

#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 / Fragment: PROTEASE
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli) / References: UniProt: Q9Y5Z0, memapsin 1
#2: Protein XAPERONE


Mass: 11897.218 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)

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Non-polymers , 5 types, 542 molecules

#3: Chemical ChemComp-66F / N-{3-[(5R)-3-amino-2,5-dimethyl-1,1-dioxido-5,6-dihydro-2H-1,2,4-thiadiazin-5-yl]-4-fluorophenyl}-5-fluoropyridine-2-carboxamide


Mass: 409.410 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H17F2N5O3S / Feature type: SUBJECT OF INVESTIGATION / Comment: inhibitor*YM
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 535 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
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: 2.34 Å3/Da / Density % sol: 47.55 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 22.5 % PEG1500, 0.01 M Na Acetate pH 4.5, 0.06 M Na Citrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Oct 5, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.31→61.7 Å / Num. obs: 121628 / % possible obs: 96 % / Redundancy: 2.334 % / Biso Wilson estimate: 23.496 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.04 / Rrim(I) all: 0.051 / Χ2: 0.972 / Net I/σ(I): 11.26 / Num. measured all: 283826 / Scaling rejects: 267
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
1.31-1.562.2780.4931.9511374251144499310.8080.6497.6
1.56-1.722.2650.1485.944189819039184950.9670.19397.1
1.72-1.982.4090.06412.584440518902184350.9930.08397.5
1.98-2.412.3260.03521.273637916612156380.9960.04594.1
2.41-3.052.4990.02628.86249221046499710.9980.03395.3
3.05-3.922.4180.02532.8712001543149630.9970.03191.4
3.92-5.722.4420.02834.746861334728100.9960.03584
5.72-9.162.670.02836.182857125310700.9960.03485.4
9.16-61.72.4160.03135.057614413150.9940.03971.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0155refinement
XSCALEdata scaling
PDB_EXTRACT3.25data extraction
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.31→61.7 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.961 / SU R Cruickshank DPI: 0.0558 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.056 / ESU R Free: 0.058 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2217 6356 5.2 %RANDOM
Rwork0.1952 ---
obs0.1966 115272 96.05 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 97.52 Å2 / Biso mean: 23.868 Å2 / Biso min: 9.9 Å2
Baniso -1Baniso -2Baniso -3
1--0.76 Å2-0 Å2-0 Å2
2---0.98 Å20 Å2
3---1.75 Å2
Refinement stepCycle: final / Resolution: 1.31→61.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3633 0 43 535 4211
Biso mean--23.69 36.08 -
Num. residues----481
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.023952
X-RAY DIFFRACTIONr_bond_other_d00.023515
X-RAY DIFFRACTIONr_angle_refined_deg1.6351.9575406
X-RAY DIFFRACTIONr_angle_other_deg3.96338161
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.1135521
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.47624.065155
X-RAY DIFFRACTIONr_dihedral_angle_3_deg10.95415601
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.9791518
X-RAY DIFFRACTIONr_chiral_restr0.1050.2601
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0214539
X-RAY DIFFRACTIONr_gen_planes_other0.010.02842
LS refinement shellResolution: 1.31→1.344 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.431 443 -
Rwork0.412 8598 -
all-9041 -
obs--97.32 %

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