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- PDB-4ewo: Design and synthesis of potent hydroxyethylamine (hea) bace-1 inh... -

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Basic information

Entry
Database: PDB / ID: 4ewo
TitleDesign and synthesis of potent hydroxyethylamine (hea) bace-1 inhibitors
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / BACE / BETA-SECRETASE / STATINE / INHIBITOR / ASPARTYL PROTEASE / GLYCOPROTEIN / MEMBRANE / PROTEASE / TRANSMEMBRANE / ZYMOGEN / 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-996 / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsBorkakoti, N. / Lindberg, J. / Derbyshire, D.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Design and synthesis of potent hydroxyethylamine (HEA) BACE-1 inhibitors carrying prime side 4,5,6,7-tetrahydrobenzazole and 4,5,6,7-tetrahydropyridinoazole templates.
Authors: Sund, C. / Belda, O. / Borkakoti, N. / Lindberg, J. / Derbyshire, D. / Vrang, L. / Hamelink, E. / Hgren, C. / Woestenenk, E. / Wikstrom, K. / Eneroth, A. / Lindstrom, E. / Kalayanov, G.
History
DepositionApr 27, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 31, 2012Provider: repository / Type: Initial release

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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)43,4622
Polymers43,0221
Non-polymers4411
Water5,909328
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.072, 76.429, 104.187
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Detailsbiological unit is the same as asym.

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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: 43021.504 Da / Num. of mol.: 1 / Fragment: unp residues 61-446
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149 / Plasmid: PET11A / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-996 / N-[(2S,3R)-4-{[(4S)-2-(2,2-dimethylpropyl)-6,6-dimethyl-4,5,6,7-tetrahydro-2H-indazol-4-yl]amino}-3-hydroxy-1-phenylbutan-2-yl]acetamide


Mass: 440.621 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H40N4O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 328 / 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: 2.28 Å3/Da / Density % sol: 46.03 %
Crystal growTemperature: 299 K / Method: vapor diffusion / pH: 5
Details: 16%PEG1000, 0.1 M NAacetate, 5 % Glycerol, pH 5.0, VAPOR DIFFUSION, temperature 299K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1.072 Å
DetectorType: ADSC QUANTUM 1 / Detector: CCD / Date: Jan 28, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.072 Å / Relative weight: 1
ReflectionResolution: 1.8→61.6 Å / Num. all: 36365 / Num. obs: 36204 / % possible obs: 99.5 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
REFMAC5.5.0102refinement
PDB_EXTRACT3.11data extraction
DNAdata collection
PHASERphasing
CCP4phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→61.6 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.939 / Occupancy max: 1 / Occupancy min: 0.2 / SU B: 2.955 / SU ML: 0.091 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.137 / ESU R Free: 0.134 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2274 1805 5 %RANDOM
Rwork0.1783 ---
obs0.1808 36204 99.56 %-
all-34399 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 68.91 Å2 / Biso mean: 22.2762 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1-2.02 Å20 Å20 Å2
2---0.49 Å20 Å2
3----1.53 Å2
Refinement stepCycle: LAST / Resolution: 1.8→61.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2959 0 32 328 3319
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0260.0223330
X-RAY DIFFRACTIONr_angle_refined_deg2.1881.9634575
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.485431
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.31123.732142
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.96315536
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.2091519
X-RAY DIFFRACTIONr_chiral_restr0.1810.2505
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.0212601
X-RAY DIFFRACTIONr_mcbond_it1.4461.52049
X-RAY DIFFRACTIONr_mcangle_it2.43523361
X-RAY DIFFRACTIONr_scbond_it3.58931281
X-RAY DIFFRACTIONr_scangle_it5.74.51214
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.375 114 -
Rwork0.292 2555 -
all-2669 -
obs--99.93 %

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