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- PDB-4l7g: Diethylaminosulfur Trifluoride-Mediated Intramolecular Cyclizatio... -

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Basic information

Entry
Database: PDB / ID: 4l7g
TitleDiethylaminosulfur Trifluoride-Mediated Intramolecular Cyclization of 2-hydroxy-benzylureas to Fused Bicyclic Aminooxazoline Compounds and Evaluation of Their Biochemical Activity Against Beta-Secretase-1 (BACE1)
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 / prepulse inhibition / amyloid-beta metabolic process ...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 / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / 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 / dendrite / neuronal cell body / 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-1W0 / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.38 Å
AuthorsHuestis, M.P. / Liu, W. / Volgraf, M. / Purkey, H. / Wang, W. / Yu, C. / Wu, P. / Smith, D. / Vigers, G. / Dutcher, D. ...Huestis, M.P. / Liu, W. / Volgraf, M. / Purkey, H. / 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

Downloads & links

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Assembly

Deposited unit
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,9783
Polymers45,6031
Non-polymers3742
Water6,828379
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)72.664, 104.471, 50.076
Angle α, β, γ (deg.)90.00, 94.82, 90.00
Int Tables number5
Space group name H-MC121

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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-1W0 / (3aS,7aR)-7a-[3-(pyrimidin-5-yl)phenyl]-3a,6,7,7a-tetrahydro-4H-pyrano[4,3-d][1,3]oxazol-2-amine


Mass: 296.324 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H16N4O2
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


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


Mass: 18.015 Da / Num. of mol.: 379 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.08 Å3/Da / Density % sol: 40.77 %
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: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: RAYONIX MX-225 / Detector: CCD / Date: Nov 5, 2010
RadiationMonochromator: Diamond [111] / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 1.38→50 Å / Num. all: 76243 / Num. obs: 75939 / % possible obs: 99.6 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 3.7 %
Reflection shellResolution: 1.38→1.43 Å / % possible all: 99.8

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHASERphasing
PHENIX(phenix.refine: 1.6.4_486)refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1FKN

1fkn


Resolution: 1.38→16.633 Å / SU ML: 0.18 / σ(F): 1.35 / Phase error: 18.25 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1916 3846 5.07 %5% random
Rwork0.1544 ---
all0.1563 76394 --
obs0.1563 75898 99.38 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 63.335 Å2 / ksol: 0.442 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--5.0081 Å20 Å2-2.0666 Å2
2--1.2089 Å2-0 Å2
3---3.7992 Å2
Refinement stepCycle: LAST / Resolution: 1.38→16.633 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2937 0 26 379 3342
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0063203
X-RAY DIFFRACTIONf_angle_d1.1214375
X-RAY DIFFRACTIONf_dihedral_angle_d13.6021156
X-RAY DIFFRACTIONf_chiral_restr0.073477
X-RAY DIFFRACTIONf_plane_restr0.005569
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.38-1.39640.29641610.28492513X-RAY DIFFRACTION94
1.3964-1.41480.24961380.23972686X-RAY DIFFRACTION100
1.4148-1.43420.33411350.2462655X-RAY DIFFRACTION100
1.4342-1.45460.26421570.21792655X-RAY DIFFRACTION100
1.4546-1.47630.24331460.20392689X-RAY DIFFRACTION100
1.4763-1.49940.22121420.17942631X-RAY DIFFRACTION100
1.4994-1.52390.20351430.16072722X-RAY DIFFRACTION100
1.5239-1.55020.22581300.16072680X-RAY DIFFRACTION100
1.5502-1.57840.22091560.15422659X-RAY DIFFRACTION100
1.5784-1.60870.19651390.14412678X-RAY DIFFRACTION100
1.6087-1.64150.18381430.12852662X-RAY DIFFRACTION100
1.6415-1.67720.1531540.12192704X-RAY DIFFRACTION100
1.6772-1.71620.16631410.1192663X-RAY DIFFRACTION100
1.7162-1.7590.18081490.12122666X-RAY DIFFRACTION100
1.759-1.80650.17791240.11652703X-RAY DIFFRACTION100
1.8065-1.85960.17711370.11882679X-RAY DIFFRACTION100
1.8596-1.91960.17091230.12362716X-RAY DIFFRACTION100
1.9196-1.98810.17671610.12562650X-RAY DIFFRACTION100
1.9881-2.06750.16471510.13182687X-RAY DIFFRACTION100
2.0675-2.16140.16161290.13232676X-RAY DIFFRACTION100
2.1614-2.27510.17281520.12862710X-RAY DIFFRACTION100
2.2751-2.41730.19281430.14192654X-RAY DIFFRACTION100
2.4173-2.60320.1831290.15482698X-RAY DIFFRACTION100
2.6032-2.8640.18981380.15942711X-RAY DIFFRACTION100
2.864-3.27570.1951440.16372695X-RAY DIFFRACTION100
3.2757-4.11670.18751390.15752679X-RAY DIFFRACTION99
4.1167-16.63410.20691420.18362531X-RAY DIFFRACTION92

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