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- PDB-3qi1: Design and synthesis of hydroxyethylamine (hea) BACE-1 inhibitors... -

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Basic information

Entry
Database: PDB / ID: 3qi1
TitleDesign and synthesis of hydroxyethylamine (hea) BACE-1 inhibitors: prime side chromane-containing inhibitors
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Aspartate 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-C6A / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsYao, N.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: prime side chromane-containing inhibitors.
Authors: Ng, R.A. / Sun, M. / Bowers, S. / Hom, R.K. / Probst, G.D. / John, V. / Fang, L.Y. / Maillard, M. / Gailunas, A. / Brogley, L. / Neitz, R.J. / Tung, J.S. / Pleiss, M.A. / Konradi, A.W. / ...Authors: Ng, R.A. / Sun, M. / Bowers, S. / Hom, R.K. / Probst, G.D. / John, V. / Fang, L.Y. / Maillard, M. / Gailunas, A. / Brogley, L. / Neitz, R.J. / Tung, J.S. / Pleiss, M.A. / Konradi, A.W. / Sham, H.L. / Dappen, M.S. / Adler, M. / Yao, N. / Zmolek, W. / Nakamura, D. / Quinn, K.P. / Sauer, J.M. / Bova, M.P. / Ruslim, L. / Artis, D.R. / Yednock, T.A.
History
DepositionJan 26, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 28, 2012Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2013Group: Database references

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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)45,8952
Polymers45,3951
Non-polymers5011
Water3,855214
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)72.174, 75.506, 80.236
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 45394.871 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: BACE, BACE1, KIAA1149 / Production host: Escherichia coli (E. coli) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-C6A / N-[(2S,3R)-4-{[(2R,4S)-2-cyclopropyl-6-(2,2-dimethylpropyl)-3,4-dihydro-2H-chromen-4-yl]amino}-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl]acetamide


Mass: 500.620 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H38F2N2O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 214 / 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: 2.41 Å3/Da / Density % sol: 48.96 %
Crystal growTemperature: 295 K / pH: 4.6
Details: BACE PROTEIN AT 10MG/ML IN 100MM SODIUM BORATE BUFFER PH 8.5. 1MM COMPOUND ADDED TO PROTEIN AND INCUBATED AT 4 C FOR 3 HOURS. HANGING DROP PLATES SET UP WITH RESERVOIR SOLUTION CONTAINING 4% ...Details: BACE PROTEIN AT 10MG/ML IN 100MM SODIUM BORATE BUFFER PH 8.5. 1MM COMPOUND ADDED TO PROTEIN AND INCUBATED AT 4 C FOR 3 HOURS. HANGING DROP PLATES SET UP WITH RESERVOIR SOLUTION CONTAINING 4% PEG 8000, 100MM SODIUM ACETATE PH 4.6 THE DROPS WERE MIXED WITH 1:1 (V/V) RATIO OF PROTEIN/COMPOUND TO RESERVOIR AND INCUBATED AT ROOM TEMPERATURE FOR 2 WEEKS. VAPOR DIFFUSION, HANGING DROP, TEMPERATURE 295K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.5418
DetectorType: RIGAKU RAXIS HTC / Detector: IMAGE PLATE / Date: Jul 30, 2010 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.3→25.69 Å / Num. obs: 19292 / % possible obs: 96.2 % / Observed criterion σ(I): 1 / Redundancy: 3.89 % / Rmerge(I) obs: 0.086 / Net I/σ(I): 9.2
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 3.86 % / Rmerge(I) obs: 0.406 / Mean I/σ(I) obs: 2.3 / % possible all: 99.8

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Processing

Software
NameVersionClassification
MOLREPphasing
REFMAC5.5.0109refinement
CrystalCleardata reduction
CrystalCleardata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→25.69 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.908 / SU B: 7 / SU ML: 0.17 / Cross valid method: THROUGHOUT / ESU R: 0.368 / ESU R Free: 0.269 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26878 986 5.1 %RANDOM
Rwork0.19837 ---
obs0.20191 18250 95.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 29.646 Å2
Baniso -1Baniso -2Baniso -3
1-0.9 Å20 Å20 Å2
2---0.8 Å20 Å2
3----0.11 Å2
Refinement stepCycle: LAST / Resolution: 2.3→25.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2986 0 36 214 3236
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0220.0223103
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.8671.9594225
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.6715380
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.2423.813139
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.86915482
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.9971517
X-RAY DIFFRACTIONr_chiral_restr0.1260.2462
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0212376
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.0981.51892
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.02523056
X-RAY DIFFRACTIONr_scbond_it2.75631211
X-RAY DIFFRACTIONr_scangle_it4.2994.51166
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.433 68 -
Rwork0.329 1395 -
obs--99.8 %

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