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- PDB-4l7h: Diethylaminosulfur Trifluoride-Mediated Intramolecular Cyclizatio... -

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Basic information

Entry
Database: PDB / ID: 4l7h
TitleDiethylaminosulfur Trifluoride-Mediated Intramolecular Cyclization of 2-hydroxy-benzylureas to Fused Bicyclic Aminooxazoline Compounds and Evaluation of Their Biochemical Activity Against Beta-Secretase-1 (BACE-1)
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Aspartic 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 / amyloid-beta metabolic process / prepulse inhibition ...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 / amyloid-beta metabolic process / prepulse inhibition / detection of mechanical stimulus involved in sensory perception of pain / protein serine/threonine kinase binding / cellular response to copper ion / presynaptic modulation of chemical synaptic transmission / hippocampal mossy fiber to CA3 synapse / 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 / peptidase activity / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / aspartic-type endopeptidase activity / lysosome / early endosome / endosome membrane / endosome / membrane raft / Amyloid fiber formation / endoplasmic reticulum lumen / axon / 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-1W1 / ACETATE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsHuestis, M.P. / Liu, W. / Volgraf, M. / Purkey, H.E. / Wang, W. / Yu, C. / Wu, P. / Smith, D. / Vigers, G. / Dutcher, D. ...Huestis, M.P. / Liu, W. / Volgraf, M. / Purkey, H.E. / Wang, W. / Yu, C. / Wu, P. / Smith, D. / Vigers, G. / Dutcher, D. / Geck Do, M.K. / 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 13, 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)46,0964
Polymers45,6031
Non-polymers4933
Water3,045169
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)73.062, 104.679, 49.995
Angle α, β, γ (deg.)90.00, 94.97, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-746-

HOH

21A-758-

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: 45603.207 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-1W1 / 2-[(3aR,7aR)-2-amino-7a-(2,4-difluorophenyl)-3a,6,7,7a-tetrahydro[1,3]oxazolo[5,4-c]pyridin-5(4H)-yl]pyridine-3-carbonitrile


Mass: 355.341 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H15F2N5O
#3: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 169 / 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: 2.09 Å3/Da / Density % sol: 41.1 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 4.9
Details: 12% PEG 3350 and 0.1M NaOAc, pH 4.9, VAPOR DIFFUSION, SITTING DROP, temperature 292K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.9774 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 23, 2010
RadiationMonochromator: Si(220) Asymmetric cut single crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9774 Å / Relative weight: 1
ReflectionResolution: 1.85→50 Å / Num. all: 31965 / Num. obs: 31006 / % possible obs: 97 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 3.7 %
Reflection shellResolution: 1.85→1.92 Å / % possible all: 85.2

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERphasing
PHENIX(phenix.refine: 1.7.3_928)refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1FKN

1fkn


Resolution: 1.85→36.988 Å / SU ML: 0.26 / σ(F): 1.34 / Phase error: 28.68 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2272 1569 5.06 %5% random
Rwork0.1871 ---
all0.1892 32061 --
obs0.1892 30987 96.65 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 45.265 Å2 / ksol: 0.324 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--7.4941 Å20 Å25.3606 Å2
2---12.8877 Å20 Å2
3---22.229 Å2
Refinement stepCycle: LAST / Resolution: 1.85→36.988 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2946 0 34 169 3149
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0063097
X-RAY DIFFRACTIONf_angle_d1.1584209
X-RAY DIFFRACTIONf_dihedral_angle_d13.6291092
X-RAY DIFFRACTIONf_chiral_restr0.076455
X-RAY DIFFRACTIONf_plane_restr0.004536
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.85-1.90670.36481150.32052205X-RAY DIFFRACTION81
1.9067-1.97480.35131210.26582686X-RAY DIFFRACTION96
1.9748-2.05390.25921570.21032679X-RAY DIFFRACTION98
2.0539-2.14740.2861480.20572712X-RAY DIFFRACTION98
2.1474-2.26060.24411550.20212680X-RAY DIFFRACTION98
2.2606-2.40220.21751350.18912724X-RAY DIFFRACTION98
2.4022-2.58760.24061520.18842710X-RAY DIFFRACTION98
2.5876-2.84790.27461500.19512705X-RAY DIFFRACTION99
2.8479-3.25980.22741570.18982753X-RAY DIFFRACTION99
3.2598-4.10620.20251460.16622761X-RAY DIFFRACTION99
4.1062-36.99510.18861330.17262803X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: 16.1639 Å / Origin y: -0.4008 Å / Origin z: 10.0664 Å
111213212223313233
T0.2177 Å20.0102 Å20.0074 Å2-0.2476 Å2-0.0003 Å2--0.2053 Å2
L1.0553 °20.6608 °20.2986 °2-1.5125 °20.4707 °2--0.6803 °2
S0.0374 Å °-0.1285 Å °0.0452 Å °0.0515 Å °-0.0959 Å °0.0453 Å °0.0198 Å °-0.1023 Å °-0.0002 Å °
Refinement TLS groupSelection details: ( CHAIN A AND RESID -1:386 )

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