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- PDB-4lc7: Aminooxazoline inhibitor of BACE-1 -

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Basic information

Entry
Database: PDB / ID: 4lc7
TitleAminooxazoline inhibitor of BACE-1
ComponentsBeta-Secretase-1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Aspartyl Protease / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


memapsin 2 / Golgi-associated vesicle lumen / signaling receptor ligand precursor processing / beta-aspartyl-peptidase activity / amyloid precursor protein catabolic process / amyloid-beta formation / membrane protein ectodomain proteolysis / cellular response to manganese ion / prepulse inhibition / detection of mechanical stimulus involved in sensory perception of pain ...memapsin 2 / Golgi-associated vesicle lumen / signaling receptor ligand precursor processing / beta-aspartyl-peptidase activity / amyloid precursor protein catabolic process / amyloid-beta formation / membrane protein ectodomain proteolysis / cellular response to manganese ion / prepulse inhibition / detection of mechanical stimulus involved in sensory perception of pain / amyloid-beta metabolic process / cellular response to copper ion / hippocampal mossy fiber to CA3 synapse / presynaptic modulation of chemical synaptic transmission / multivesicular body / response to lead ion / trans-Golgi network / protein processing / recycling endosome / cellular response to amyloid-beta / positive regulation of neuron apoptotic process / synaptic vesicle / late endosome / amyloid-beta binding / peptidase activity / endopeptidase activity / amyloid fibril formation / lysosome / aspartic-type endopeptidase activity / early endosome / endosome membrane / endosome / membrane raft / Amyloid fiber formation / axon / endoplasmic reticulum lumen / neuronal cell body / dendrite / Golgi apparatus / enzyme binding / cell surface / 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-1WP / NICKEL (II) ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsHuestis, M.P. / Liu, W. / Volgraf, M. / Purkey, H.E. / Wu, C. / Wang, W. / Smith, D. / Vigers, G.P.A. / Dutcher, D. / Hunt, K.W. / Siu, M.
CitationJournal: Tetrahedron Lett. / Year: 2013
Title: Diethylaminosulfur Trifluoride-Mediated Intramolecular Cyclization of 2-hydroxycycloalkylureas to Fused Bicyclic Aminooxazoline Compounds and Evaluation of Their Biochemical Activity Against ...Title: Diethylaminosulfur Trifluoride-Mediated Intramolecular Cyclization of 2-hydroxycycloalkylureas to Fused Bicyclic Aminooxazoline Compounds and Evaluation of Their Biochemical Activity Against β-Secretase-1 (BACE-1)
Authors: Huestis, M.P. / Liu, W. / Volgraf, M. / Purkey, H. / Yu, C. / Wang, W. / Smith, D. / Vigers, G. / Dutcher, D. / Hunt, K.W. / Siu, M.
History
DepositionJun 21, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 18, 2013Provider: repository / Type: Initial release
Revision 1.1Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Beta-Secretase-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,8323
Polymers45,4451
Non-polymers3872
Water2,756153
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)74.938, 103.900, 100.498
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-691-

HOH

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Components

#1: Protein Beta-Secretase-1 / / Aspartyl protease 2 / ASP2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta- ...Aspartyl protease 2 / ASP2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta-site APP cleaving enzyme 1 / Memapsin-2 / Membrane-associated aspartic protease 2


Mass: 45445.121 Da / Num. of mol.: 1 / Fragment: UNP residues 57-453
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-NI / NICKEL (II) ION / Nickel


Mass: 58.693 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ni
#3: Chemical ChemComp-1WP / (3aR,7aR)-3a-[3-(5-chloropyridin-3-yl)phenyl]-3a,4,5,6,7,7a-hexahydro-1,3-benzoxazol-2-amine


Mass: 327.808 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H18ClN3O
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 153 / Source method: isolated from a natural source / Formula: H2O

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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: 2.15 Å3/Da / Density % sol: 42.85 %
Crystal growTemperature: 279 K / Method: vapor diffusion, hanging drop / pH: 4.5
Details: 16% PEG3K, 0.1M NaAcetate pH 4.5, 5% DMSO, VAPOR DIFFUSION, HANGING DROP, temperature 279K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Aug 26, 2010 / Details: Confocal mirrors
RadiationMonochromator: Confocal mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.7→30 Å / Num. all: 43268 / Num. obs: 40513 / % possible obs: 93.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 2 / Redundancy: 7.2 % / Rmerge(I) obs: 0.108 / Rsym value: 0.099 / Net I/σ(I): 12.4
Reflection shellResolution: 1.7→1.8 Å / Redundancy: 5.9 % / Rmerge(I) obs: 0.303 / Mean I/σ(I) obs: 2.8 / Num. unique all: 6191 / Rsym value: 0.303 / % possible all: 74.8

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPphasing
REFMAC5.7.0029refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4JP9

4jp9


Resolution: 1.7→14.78 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.942 / SU B: 2.266 / SU ML: 0.077 / Cross valid method: THROUGHOUT / ESU R: 0.13 / ESU R Free: 0.124 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.23692 2029 5 %RANDOM
Rwork0.20156 ---
obs0.20328 38458 93.21 %-
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: 28.203 Å2
Baniso -1Baniso -2Baniso -3
1--0.55 Å20 Å2-0 Å2
2---1.42 Å2-0 Å2
3---1.97 Å2
Refinement stepCycle: LAST / Resolution: 1.7→14.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3163 0 24 153 3340
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0193275
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.2761.954458
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4535401
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.8823.882152
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.84615514
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.481518
X-RAY DIFFRACTIONr_chiral_restr0.0880.2479
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212526
X-RAY DIFFRACTIONr_gen_planes_other
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: 1.7→1.744 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.302 100 -
Rwork0.292 1884 -
obs--63.67 %

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