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- PDB-5clm: 1,4-Oxazine BACE1 inhibitors -

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Basic information

Entry
Database: PDB / ID: 5clm
Title1,4-Oxazine BACE1 inhibitors
ComponentsBeta-secretase 1
KeywordsHYDROLASE / BACE1 PROTEASE Inhibitor / orally bioavailable / brain penetrant / PROTEROS BIOSTRUCTURES GMBH
Function / homology
Function and homology information


memapsin 2 / Golgi-associated vesicle lumen / beta-aspartyl-peptidase activity / signaling receptor ligand precursor processing / amyloid precursor protein catabolic process / amyloid-beta formation / membrane protein ectodomain proteolysis / amyloid-beta metabolic process / cellular response to manganese ion / prepulse inhibition ...memapsin 2 / Golgi-associated vesicle lumen / beta-aspartyl-peptidase activity / signaling receptor ligand precursor processing / amyloid precursor protein catabolic process / amyloid-beta formation / membrane protein ectodomain proteolysis / amyloid-beta metabolic process / cellular response to manganese ion / prepulse inhibition / detection of mechanical stimulus involved in sensory perception of pain / cellular response to copper ion / protein serine/threonine kinase binding / presynaptic modulation of chemical synaptic transmission / multivesicular body / hippocampal mossy fiber to CA3 synapse / trans-Golgi network / response to lead ion / protein processing / recycling endosome / cellular response to amyloid-beta / positive regulation of neuron apoptotic process / late endosome / synaptic vesicle / peptidase activity / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / aspartic-type endopeptidase activity / early endosome / lysosome / endosome / endosome membrane / membrane raft / Amyloid fiber formation / endoplasmic reticulum lumen / axon / neuronal cell body / dendrite / enzyme binding / cell surface / Golgi apparatus / proteolysis / membrane / plasma membrane
Similarity search - Function
Beta-secretase BACE1 / 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 BACE1 / 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-52K / IODIDE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.61 Å
AuthorsRombouts, F. / Tresadern, G. / Delgado, O. / Martinez Lamenca, C. / Van Gool, M. / Garcia-Molina, A. / Alonso De Diego, S. / Oehlrich, D. / Prokopcova, H. / Alonso, J.M. ...Rombouts, F. / Tresadern, G. / Delgado, O. / Martinez Lamenca, C. / Van Gool, M. / Garcia-Molina, A. / Alonso De Diego, S. / Oehlrich, D. / Prokopcova, H. / Alonso, J.M. / Austin, N. / Borghys, H. / Van Brandt, S. / Surkyn, M. / De Cleyn, M. / Vos, A. / Alexander, R. / MacDonald, G. / Moechars, D. / Trabanco, A. / Gijsen, H.
CitationJournal: J.Med.Chem. / Year: 2015
Title: 1,4-Oxazine beta-Secretase 1 (BACE1) Inhibitors: From Hit Generation to Orally Bioavailable Brain Penetrant Leads.
Authors: Rombouts, F.J. / Tresadern, G. / Delgado, O. / Martinez-Lamenca, C. / Van Gool, M. / Garcia-Molina, A. / Alonso de Diego, S.A. / Oehlrich, D. / Prokopcova, H. / Alonso, J.M. / Austin, N. / ...Authors: Rombouts, F.J. / Tresadern, G. / Delgado, O. / Martinez-Lamenca, C. / Van Gool, M. / Garcia-Molina, A. / Alonso de Diego, S.A. / Oehlrich, D. / Prokopcova, H. / Alonso, J.M. / Austin, N. / Borghys, H. / Van Brandt, S. / Surkyn, M. / De Cleyn, M. / Vos, A. / Alexander, R. / Macdonald, G. / Moechars, D. / Gijsen, H. / Trabanco, A.A.
History
DepositionJul 16, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Sep 30, 2015Provider: repository / Type: Initial release
Revision 1.1Nov 4, 2015Group: Database references
Revision 1.2Oct 23, 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,3896
Polymers44,6281
Non-polymers7615
Water1,35175
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area520 Å2
ΔGint-5 kcal/mol
Surface area16110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)100.824, 100.824, 170.104
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122

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Components

#1: Protein Beta-secretase 1 / Aspartyl protease 2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta-site APP ...Aspartyl protease 2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta-site APP cleaving enzyme 1 / Memapsin-2 / Membrane-associated aspartic protease 2


Mass: 44628.051 Da / Num. of mol.: 1 / Fragment: PROTEASE, UNP residues 46-446 / Mutation: R11T, R12T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149 / Production host: Escherichia coli (E. coli) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-52K / N-{3-[(3R)-5-amino-3-methyl-3,6-dihydro-2H-1,4-oxazin-3-yl]phenyl}-5-chloropyridine-2-carboxamide


Mass: 344.795 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H17ClN4O2
#3: Chemical ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: I
#4: Chemical ChemComp-CL / CHLORIDE ION


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


Mass: 18.015 Da / Num. of mol.: 75 / Source method: isolated from a natural source / Formula: H2O
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: 2.87 Å3/Da / Density % sol: 57.11 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 12% (m/v) PEG4000, 100mM MES/NaOH pH 5.5 / PH range: 5.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 2, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→87.32 Å / Num. obs: 16235 / % possible obs: 99 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 15.3 % / Biso Wilson estimate: 54.499 Å2 / Rmerge(I) obs: 0.093 / Net I/σ(I): 24.85
Reflection shellResolution: 2.6→2.77 Å / Redundancy: 15.6 % / Rmerge(I) obs: 0.797 / % possible all: 94.5

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.6.0117refinement
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.61→87.32 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.909 / SU B: 9.292 / SU ML: 0.201 / Cross valid method: THROUGHOUT / ESU R: 0.499 / ESU R Free: 0.296 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25003 820 5.1 %RANDOM
Rwork0.1902 ---
obs0.19317 15381 99.94 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 49.026 Å2
Baniso -1Baniso -2Baniso -3
1-0.66 Å20.33 Å20 Å2
2--0.66 Å20 Å2
3----0.99 Å2
Refinement stepCycle: LAST / Resolution: 2.61→87.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2959 0 28 75 3062
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.023062
X-RAY DIFFRACTIONr_bond_other_d0.0020.022046
X-RAY DIFFRACTIONr_angle_refined_deg1.1711.9564165
X-RAY DIFFRACTIONr_angle_other_deg0.9833.0024956
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0665373
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.40823.813139
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.72715483
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.9391517
X-RAY DIFFRACTIONr_chiral_restr0.0680.2452
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0213420
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02658
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.61→2.678 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.394 58 -
Rwork0.281 960 -
obs--100 %

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