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Yorodumi- PDB-4i0z: Structure-based design of novel dihydroisoquinoline BACE-1 inhibi... -
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-Basic information
Entry | Database: PDB / ID: 4i0z | ||||||
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Title | Structure-based design of novel dihydroisoquinoline BACE-1 inhibitors that do not engage the catalytic aspartates | ||||||
Components | 2-{(1S)-1-[(6-CHLORO-3,3-DIMETHYL-3,4-DIHYDROISOQUINOLIN-1-YL)AMINO]-2-PHENYLETHYL}-4-OXO-1,4-DIHYDROPYRIMIDINE-5-CARBONITRILE | ||||||
Keywords | hydrolase/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 / 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 / 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 / recycling endosome / protein processing / 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 / 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 | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.8 Å | ||||||
Authors | Lougheed, J.C. / Brecht, E. / Yao, N.H. | ||||||
Citation | Journal: Bioorg.Med.Chem.Lett. / Year: 2013 Title: Structure-based design of novel dihydroisoquinoline BACE-1 inhibitors that do not engage the catalytic aspartates. Authors: Bowers, S. / Xu, Y.Z. / Yuan, S. / Probst, G.D. / Hom, R.K. / Chan, W. / Konradi, A.W. / Sham, H.L. / Zhu, Y.L. / Beroza, P. / Pan, H. / Brecht, E. / Yao, N. / Lougheed, J. / Tam, D. / Ren, ...Authors: Bowers, S. / Xu, Y.Z. / Yuan, S. / Probst, G.D. / Hom, R.K. / Chan, W. / Konradi, A.W. / Sham, H.L. / Zhu, Y.L. / Beroza, P. / Pan, H. / Brecht, E. / Yao, N. / Lougheed, J. / Tam, D. / Ren, Z. / Ruslim, L. / Bova, M.P. / Artis, D.R. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 4i0z.cif.gz | 94.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb4i0z.ent.gz | 75.6 KB | Display | PDB format |
PDBx/mmJSON format | 4i0z.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/i0/4i0z ftp://data.pdbj.org/pub/pdb/validation_reports/i0/4i0z | HTTPS FTP |
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-Related structure data
-Links
-Assembly
Deposited unit |
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1 |
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2 |
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Unit cell |
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-Components
#1: Protein | Mass: 45445.121 Da / Num. of mol.: 1 / Fragment: unp residues 57-453 / Source method: obtained synthetically / Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149 / Production host: Escherichia coli (E. coli) / References: UniProt: P56817, memapsin 2 | ||
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#2: Chemical | ChemComp-1BB / | ||
#3: Chemical | ChemComp-ZN / #4: Water | ChemComp-HOH / | |
-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.14 Å3/Da / Density % sol: 42.58 % |
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Crystal grow | Temperature: 277 K / Method: vapor diffusion, sitting drop / pH: 5.3 Details: 9% PEG 8000, 100mM sodium acetate, 10mM ZnCl2, VAPOR DIFFUSION, SITTING DROP, temperature 277K, pH 5.3 |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å |
Detector | Type: RIGAKU SATURN 944+ / Detector: CCD / Date: Dec 19, 2011 |
Radiation | Monochromator: mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1.5418 Å / Relative weight: 1 |
Reflection | Resolution: 1.8→60 Å / Num. all: 36583 / Num. obs: 33721 / % possible obs: 92.3 % |
Reflection shell | Resolution: 1.8→1.88 Å / % possible all: 53 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→60 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.936 / SU B: 2.913 / SU ML: 0.093 / Cross valid method: THROUGHOUT / ESU R: 0.166 / ESU R Free: 0.151 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 27.988 Å2
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Refinement step | Cycle: LAST / Resolution: 1.8→60 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 1.8→1.847 Å / Total num. of bins used: 20
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