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- PDB-3ufl: Discovery of Pyrrolidine-based b-Secretase Inhibitors: Lead Advan... -

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Basic information

Entry
Database: PDB / ID: 3ufl
TitleDiscovery of Pyrrolidine-based b-Secretase Inhibitors: Lead Advancement through Conformational Design for Maintenance of Ligand Binding Efficiency
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 / amyloid-beta metabolic process / cellular response to manganese ion / 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 / amyloid-beta metabolic process / cellular response to manganese ion / 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 / multivesicular body / hippocampal mossy fiber to CA3 synapse / response to lead ion / trans-Golgi network / recycling endosome / protein processing / 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 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-508 / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsAllison, T. / Munshi, S. / Soisson, S.M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Discovery of pyrrolidine-based beta-secretase inhibitors: Lead advancement through conformational design for maintenance of ligand binding efficiency.
Authors: Stachel, S.J. / Steele, T.G. / Petrocchi, A. / Haugabook, S.J. / McGaughey, G. / Katharine Holloway, M. / Allison, T. / Munshi, S. / Zuck, P. / Colussi, D. / Tugasheva, K. / Wolfe, A. / ...Authors: Stachel, S.J. / Steele, T.G. / Petrocchi, A. / Haugabook, S.J. / McGaughey, G. / Katharine Holloway, M. / Allison, T. / Munshi, S. / Zuck, P. / Colussi, D. / Tugasheva, K. / Wolfe, A. / Graham, S.L. / Vacca, J.P.
History
DepositionNov 1, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 18, 2012Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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)44,3328
Polymers43,3131
Non-polymers1,0197
Water5,549308
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)103.668, 127.642, 76.846
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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Components

#1: Protein Beta-secretase 1 / BACE1 / Aspartyl protease 2 / ASP2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 ...BACE1 / 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: 43312.805 Da / Num. of mol.: 1 / Fragment: UNP residues 58-446
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149 / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-508 / (1R,4'S)-3,4-dihydro-2H-spiro[naphthalene-1,3'-pyrrolidin]-4'-yl[(2S,4R)-2,4-diphenylpiperidin-1-yl]methanone


Mass: 450.614 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H34N2O
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 308 / 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: 2.99 Å3/Da / Density % sol: 58.81 %
Crystal growTemperature: 273 K / Method: vapor diffusion, hanging drop / pH: 7
Details: pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 273K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Nov 5, 2007
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. all: 40327 / Num. obs: 39870 / % possible obs: 98.9 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 6.6 % / Rmerge(I) obs: 0.072 / Χ2: 1.068 / Net I/σ(I): 10.1
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
1.9-1.974.50.45736751.271192
1.97-2.055.40.35638660.925197.6
2.05-2.146.10.32139631.182199.7
2.14-2.256.50.26740021.34199.8
2.25-2.3970.23239971.131199.9
2.39-2.587.30.17439961.0241100
2.58-2.847.40.11840310.9641100
2.84-3.257.40.06540390.9021100
3.25-4.097.40.0440801.1411100
4.09-507.10.02542210.92199.8

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMAC5.2.0019refinement
PDB_EXTRACT3.1data extraction
ADSCQuantumdata collection
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→31.91 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.932 / Occupancy max: 1 / Occupancy min: 0.3 / SU B: 4.501 / SU ML: 0.124 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.151 / ESU R Free: 0.141 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2454 2038 5.1 %RANDOM
Rwork0.2122 ---
all0.2139 40327 --
obs0.2139 39826 98.72 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 95.33 Å2 / Biso mean: 29.8936 Å2 / Biso min: 7.39 Å2
Baniso -1Baniso -2Baniso -3
1--0.23 Å20 Å20 Å2
2--0.44 Å20 Å2
3----0.21 Å2
Refinement stepCycle: LAST / Resolution: 1.9→31.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2927 0 66 308 3301
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0223074
X-RAY DIFFRACTIONr_angle_refined_deg1.1581.9684183
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.285372
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.67223.723137
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.8615475
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.6761517
X-RAY DIFFRACTIONr_chiral_restr0.0890.2449
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.022344
X-RAY DIFFRACTIONr_nbd_refined0.1860.21379
X-RAY DIFFRACTIONr_nbtor_refined0.310.22035
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1230.2258
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2370.275
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1520.235
X-RAY DIFFRACTIONr_mcbond_it0.6171.51904
X-RAY DIFFRACTIONr_mcangle_it1.09723002
X-RAY DIFFRACTIONr_scbond_it1.15831344
X-RAY DIFFRACTIONr_scangle_it1.9794.51180
LS refinement shellResolution: 1.9→1.952 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.405 127 -
Rwork0.369 2520 -
all-2647 -
obs--89.85 %

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