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- PDB-4b78: Aminoimidazoles as BACE-1 Inhibitors: From De Novo Design to Ab- ... -

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Basic information

Entry
Database: PDB / ID: 4b78
TitleAminoimidazoles as BACE-1 Inhibitors: From De Novo Design to Ab- lowering in Brain
ComponentsBETA-SECRETASE 1
KeywordsHYDROLASE / HYDROLASE INHIBITOR / LEAD GENERATION / STRUCTURE-BASED DRUG DESIGN
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-KGG / Beta-secretase 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsGravenfors, Y. / Blid, J. / Ginman, T. / Karlstrom, S. / Kihlstrom, J. / Kolmodin, K. / Lindstrom, J. / Berg, S. / Kieseritzky, F. / Slivo, C. ...Gravenfors, Y. / Blid, J. / Ginman, T. / Karlstrom, S. / Kihlstrom, J. / Kolmodin, K. / Lindstrom, J. / Berg, S. / Kieseritzky, F. / Slivo, C. / Swahn, B. / Viklund, J. / Olsson, L. / Johansson, P. / Eketjall, S. / Falting, J. / Jeppsson, F. / Stromberg, K. / Janson, J. / Rahm, F.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Core Refinement Toward Permeable Beta-Secretase (Bace-1) Inhibitors with Low Herg Activity.
Authors: Ginman, T. / Viklund, J. / Malmstrom, J. / Blid, J. / Emond, R. / Forsblom, R. / Johansson, A. / Kers, A. / Lake, F. / Sehgelmeble, F. / Sterky, K.J. / Bergh, M. / Lindgren, A. / Johansson, ...Authors: Ginman, T. / Viklund, J. / Malmstrom, J. / Blid, J. / Emond, R. / Forsblom, R. / Johansson, A. / Kers, A. / Lake, F. / Sehgelmeble, F. / Sterky, K.J. / Bergh, M. / Lindgren, A. / Johansson, P. / Jeppsson, F. / Falting, J. / Gravenfors, Y. / Rahm, F.
History
DepositionAug 16, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 26, 2013Provider: repository / Type: Initial release
Revision 1.1Jul 3, 2013Group: Database references
Remark 700 SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN ... SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN THE SHEET RECORDS BELOW, TWO SHEETS ARE DEFINED.

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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)43,1822
Polymers42,8081
Non-polymers3731
Water6,720373
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)47.697, 74.107, 104.739
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: 42808.273 Da / Num. of mol.: 1 / Fragment: RESIDUES 62-445
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-KGG / (3R,5R)-3-methoxy-5-(4-methoxyphenyl)-5-(3-pyridin-3-ylphenyl)-3,4-dihydropyrrol-2-amine


Mass: 373.448 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H23N3O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 373 / 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: 2.3 Å3/Da / Density % sol: 46 % / Description: NONE
Crystal growpH: 7 / Details: pH 7

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1.003
DetectorType: ADSC CCD / Detector: CCD / Date: Sep 26, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.003 Å / Relative weight: 1
ReflectionResolution: 1.5→37.46 Å / Num. obs: 60068 / % possible obs: 99.7 % / Observed criterion σ(I): 1 / Redundancy: 3.5 % / Rmerge(I) obs: 0.07 / Net I/σ(I): 8.6
Reflection shellResolution: 1.5→1.54 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.55 / Mean I/σ(I) obs: 1.9 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.5→30 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.929 / SU B: 1.587 / SU ML: 0.06 / Cross valid method: THROUGHOUT / ESU R: 0.093 / ESU R Free: 0.091 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.23412 2876 5.1 %RANDOM
Rwork0.20622 ---
obs0.20762 54068 94.52 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 17.944 Å2
Baniso -1Baniso -2Baniso -3
1-1.3 Å20 Å20 Å2
2---0.46 Å20 Å2
3----0.84 Å2
Refinement stepCycle: LAST / Resolution: 1.5→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2928 0 28 373 3329
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.023097
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.5861.9574224
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7735386
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.54423.786140
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.96115495
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.4171518
X-RAY DIFFRACTIONr_chiral_restr0.1020.2457
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0212435
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_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.5→1.539 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.338 199 -
Rwork0.29 3475 -
obs--87.33 %

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