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- PDB-7n4n: BACE-2 in complex with ligand 36 -

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Basic information

Entry
Database: PDB / ID: 7n4n
TitleBACE-2 in complex with ligand 36
Components
  • Beta-secretase 2
  • Xaperone
KeywordsHYDROLASE/INHIBITOR / BACE PROTEASE / HYDROLASE / HYDROLASE-INHIBITOR 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-0BK / Beta-secretase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.41 Å
AuthorsShaffer, P.L.
CitationJournal: J.Med.Chem. / Year: 2021
Title: JNJ-67569762, A 2-Aminotetrahydropyridine-Based Selective BACE1 Inhibitor Targeting the S3 Pocket: From Discovery to Clinical Candidate.
Authors: Rombouts, F.J.R. / Kusakabe, K.I. / Alexander, R. / Austin, N. / Borghys, H. / De Cleyn, M. / Dhuyvetter, D. / Gijsen, H.J.M. / Hrupka, B. / Jacobs, T. / Jerhaoui, S. / Lammens, L. / ...Authors: Rombouts, F.J.R. / Kusakabe, K.I. / Alexander, R. / Austin, N. / Borghys, H. / De Cleyn, M. / Dhuyvetter, D. / Gijsen, H.J.M. / Hrupka, B. / Jacobs, T. / Jerhaoui, S. / Lammens, L. / Leclercq, L. / Tsubone, K. / Ueno, T. / Morimoto, K. / Einaru, S. / Sumiyoshi, H. / Van den Bergh, A. / Vos, A. / Surkyn, M. / Teisman, A. / Moechars, D.
History
DepositionJun 4, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 6, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 27, 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)54,9287
Polymers54,2122
Non-polymers7165
Water8,467470
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)63.757, 74.492, 109.361
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 / ASP1 / Asp 1 / Beta-site amyloid precursor ...Aspartic-like protease 56 kDa / Aspartyl protease 1 / ASP1 / 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-0BK / N-{3-[(2S,5R)-6-amino-2-(fluoromethyl)-5-(methanesulfonyl)-5-methyl-2,3,4,5-tetrahydropyridin-2-yl]-4-fluorophenyl}-6-methoxypyrimidine-4-carboxamide


Mass: 467.490 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H23F2N5O4S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 470 / 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: 2.32 Å3/Da / Density % sol: 46.96 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 22.5% PEG-1500, 25 mM Bis-Tris Propane pH 7.0, 150 mM NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99998 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 16, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99998 Å / Relative weight: 1
ReflectionResolution: 1.41→61.57 Å / Num. obs: 96877 / % possible obs: 96 % / Redundancy: 2.4 % / Biso Wilson estimate: 25.979 Å2 / Rmerge(I) obs: 0.039 / Rrim(I) all: 0.05 / Χ2: 0.979 / Net I/σ(I): 11.89
Reflection shellResolution: 1.41→1.66 Å / Redundancy: 2.3 % / Rmerge(I) obs: 0.483 / Mean I/σ(I) obs: 1.94 / Num. unique obs: 37911 / Rrim(I) all: 0.624 / % possible all: 98

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.2.0005refinement
PDB_EXTRACT3.27data extraction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.41→61.57 Å / Cor.coef. Fo:Fc: 0.977 / Cor.coef. Fo:Fc free: 0.965 / SU B: 4.165 / SU ML: 0.065 / SU R Cruickshank DPI: 0.0679 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.066 / ESU R Free: 0.063 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.207 5087 5.3 %RANDOM
Rwork0.163 ---
obs-91788 96.02 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 73.51 Å2 / Biso mean: 25.057 Å2 / Biso min: 7.36 Å2
Baniso -1Baniso -2Baniso -3
1--0.97 Å2-0 Å2-0 Å2
2---1.37 Å20 Å2
3---2.35 Å2
Refinement stepCycle: final / Resolution: 1.41→61.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3668 0 91 470 4229
Biso mean--30.8 35.92 -
Num. residues----478
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.023974
X-RAY DIFFRACTIONr_bond_other_d0.0040.023652
X-RAY DIFFRACTIONr_angle_refined_deg1.5881.9585439
X-RAY DIFFRACTIONr_angle_other_deg1.41738397
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6635523
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.42923.734158
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.23715602
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.0981521
X-RAY DIFFRACTIONr_chiral_restr0.0970.2603
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0214646
X-RAY DIFFRACTIONr_gen_planes_other0.0040.02938
X-RAY DIFFRACTIONr_rigid_bond_restr11.08237626
X-RAY DIFFRACTIONr_sphericity_free18.5175295
X-RAY DIFFRACTIONr_sphericity_bonded7.37457693
LS refinement shellResolution: 1.41→1.447 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.393 372 -
Rwork0.327 6828 -
all-7200 -
obs--97.75 %

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