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- PDB-4dpf: BACE-1 in complex with a HEA-macrocyclic type inhibitor -

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Basic information

Entry
Database: PDB / ID: 4dpf
TitleBACE-1 in complex with a HEA-macrocyclic type inhibitor
ComponentsBeta-secretase 1
KeywordsHydrolase/Hydrolase inhibitor / BACE1 / ASP2 / BACE / macrocycle / 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 / detection of mechanical stimulus involved in sensory perception of pain / amyloid-beta metabolic process / cellular response to manganese ion ...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 / detection of mechanical stimulus involved in sensory perception of pain / amyloid-beta metabolic process / cellular response to manganese ion / prepulse inhibition / 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 / positive regulation of neuron apoptotic process / cellular response to amyloid-beta / late endosome / synaptic vesicle / peptidase activity / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / lysosome / aspartic-type endopeptidase activity / 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-0LG / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.8 Å
AuthorsLindberg, J. / Borkakoti, N. / Derbyshire, D.
CitationJournal: Bioorg.Med.Chem. / Year: 2012
Title: Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core: design, synthesis and X-ray crystal structures of enzyme inhibitor complexes.
Authors: Sandgren, V. / Agback, T. / Johansson, P.O. / Lindberg, J. / Kvarnstrom, I. / Samuelsson, B. / Belda, O. / Dahlgren, A.
History
DepositionFeb 13, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 11, 2012Provider: repository / Type: Initial release
Revision 1.1Jan 2, 2013Group: Database references
Revision 1.2Oct 16, 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_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)44,2502
Polymers43,6011
Non-polymers6491
Water3,873215
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)47.760, 76.710, 103.880
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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: 43601.195 Da / Num. of mol.: 1 / Fragment: unp residues 57-446
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149 / Plasmid: pET21 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-0LG / N-[(4S,8E,11S)-4-[(1R)-1-hydroxy-2-{[3-(propan-2-yl)benzyl]amino}ethyl]-2,13-dioxo-11-phenyl-6-oxa-3,12-diazabicyclo[12.3.1]octadeca-1(18),8,14,16-tetraen-16-yl]-N-methylmethanesulfonamide


Mass: 648.812 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C35H44N4O6S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 215 / 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: 2.18 Å3/Da / Density % sol: 43.63 %
Crystal growTemperature: 291 K / Method: vapor diffusion / pH: 4.5
Details: 18% PEG 1000, 0.1 Na-Acetate pH4.5, 5% Glycerol, vapor diffusion, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.976 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 29, 2011 / Details: Mirrors
RadiationMonochromator: Graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 1.8→51.94 Å / Num. all: 36162 / Num. obs: 35772 / % possible obs: 98.9 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Rmerge(I) obs: 0.077
Reflection shellResolution: 1.8→1.9 Å / Redundancy: 2.2 % / Rmerge(I) obs: 0.325 / Mean I/σ(I) obs: 2.3 / Num. unique all: 4817 / % possible all: 93.2

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 39.71 / Model details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å51.94 Å
Translation2.5 Å51.94 Å

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
PHASER2.1.4phasing
REFMACrefinement
PDB_EXTRACT3.1data extraction
DNAdata collection
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→43.39 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.933 / WRfactor Rfree: 0.2412 / WRfactor Rwork: 0.1917 / Occupancy max: 1 / Occupancy min: 0.3 / FOM work R set: 0.8418 / SU B: 6.981 / SU ML: 0.098 / SU R Cruickshank DPI: 0.1411 / SU Rfree: 0.1374 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.141 / ESU R Free: 0.137 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2393 1785 5 %RANDOM
Rwork0.192 ---
obs0.1944 35714 98.77 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 58.31 Å2 / Biso mean: 20.5565 Å2 / Biso min: 5.1 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 1.8→43.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2950 0 46 215 3211
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0250.0223190
X-RAY DIFFRACTIONr_angle_refined_deg2.031.9664368
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.085405
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.10823.611144
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.33715514
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.5671520
X-RAY DIFFRACTIONr_chiral_restr0.1590.2482
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.0212467
X-RAY DIFFRACTIONr_mcbond_it1.3391.51916
X-RAY DIFFRACTIONr_mcangle_it2.23623127
X-RAY DIFFRACTIONr_scbond_it3.48831274
X-RAY DIFFRACTIONr_scangle_it5.284.51226
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.383 100 -
Rwork0.311 2282 -
all-2382 -
obs--89.65 %
Refinement TLS params.Method: refined / Origin x: -2.375 Å / Origin y: 1.4164 Å / Origin z: -14.971 Å
111213212223313233
T0.0066 Å2-0.0064 Å20.0013 Å2-0.0399 Å2-0.0045 Å2--0.0622 Å2
L0.1421 °2-0.0755 °2-0.0783 °2-0.3862 °2-0.0423 °2--0.8086 °2
S0.0181 Å °0.0144 Å °-0.0059 Å °0.0113 Å °0.0076 Å °0.0166 Å °0.0227 Å °-0.0582 Å °-0.0258 Å °

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