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- PDB-4b1c: New Aminoimidazoles as BACE-1 Inhibitors: From Rational Design to... -

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Basic information

Entry
Database: PDB / ID: 4b1c
TitleNew Aminoimidazoles as BACE-1 Inhibitors: From Rational Design to Ab- lowering in Brain
ComponentsBETA-SECRETASE 1
KeywordsHYDROLASE / LEAD GENERATION / STRUCTURE-BASED DRUG DESIGN / INHIBITOR
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 / prepulse inhibition / amyloid-beta metabolic process ...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 / prepulse inhibition / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / cellular response to copper ion / hippocampal mossy fiber to CA3 synapse / presynaptic modulation of chemical synaptic transmission / 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 / amyloid-beta binding / peptidase activity / endopeptidase activity / amyloid fibril formation / lysosome / aspartic-type endopeptidase activity / early endosome / endosome membrane / endosome / membrane raft / Amyloid fiber formation / axon / endoplasmic reticulum lumen / dendrite / neuronal cell body / 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-1B1 / Beta-secretase 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsRahm, F. / Blid, J. / Ginman, T. / Karlstrom, S. / Kihlstrom, J. / Kolmodin, K. / Lindstrom, J. / von Berg, S. / von Kieseritzky, F. / Slivo, C. ...Rahm, F. / Blid, J. / Ginman, T. / Karlstrom, S. / Kihlstrom, J. / Kolmodin, K. / Lindstrom, J. / von Berg, S. / von Kieseritzky, F. / Slivo, C. / Swahn, B. / Viklund, J. / Olsson, L. / Johansson, P. / Eketjall, S. / Falting, J. / Jeppsson, F. / Stromberg, K. / Janson, J. / Gravenfors, Y.
CitationJournal: J. Med. Chem. / Year: 2012
Title: New aminoimidazoles as beta-secretase (BACE-1) inhibitors showing amyloid-beta (A beta ) lowering in brain.
Authors: Gravenfors, Y. / Viklund, J. / Blid, J. / Ginman, T. / Karlstrom, S. / Kihlstrom, J. / Kolmodin, K. / Lindstrom, J. / von Berg, S. / von Kieseritzky, F. / Bogar, K. / Slivo, C. / Swahn, B.M. ...Authors: Gravenfors, Y. / Viklund, J. / Blid, J. / Ginman, T. / Karlstrom, S. / Kihlstrom, J. / Kolmodin, K. / Lindstrom, J. / von Berg, S. / von Kieseritzky, F. / Bogar, K. / Slivo, C. / Swahn, B.M. / Olsson, L.L. / Johansson, P. / Eketjall, S. / Falting, J. / Jeppsson, F. / Stromberg, K. / Janson, J. / Rahm, F.
History
DepositionJul 10, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 10, 2012Provider: repository / Type: Initial release
Revision 1.1Nov 21, 2012Group: Database references
Revision 1.2Feb 14, 2018Group: Database references / Structure summary / Category: audit_author / citation / citation_author
Item: _audit_author.name / _citation.journal_abbrev ..._audit_author.name / _citation.journal_abbrev / _citation.journal_id_ISSN / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.title

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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)42,3183
Polymers41,9111
Non-polymers4072
Water4,684260
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)47.960, 75.596, 104.523
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: 41911.312 Da / Num. of mol.: 1 / Fragment: RESIDUES 56-445
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-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#3: Chemical ChemComp-1B1 / (2R)-2-cyclopropyl-5-methyl-2-[3-(5-prop-1-yn-1-ylpyridin-3-yl)phenyl]-2H-imidazol-4-amine


Mass: 328.410 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H20N4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 260 / 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

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Wavelength: 1.54
DetectorType: MARRESEARCH / Detector: CCD / Date: Oct 26, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.95→26.41 Å / Num. obs: 27406 / % possible obs: 96.7 % / Observed criterion σ(I): 2 / Redundancy: 3.5 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 14
Reflection shellResolution: 1.95→2 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.43 / Mean I/σ(I) obs: 2.1 / % possible all: 93.5

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Processing

Software
NameVersionClassification
REFMAC5.5.0066refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.95→61.2 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.923 / SU B: 4.46 / SU ML: 0.12 / Cross valid method: THROUGHOUT / ESU R: 0.2 / ESU R Free: 0.18 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.24459 1304 5 %RANDOM
Rwork0.18802 ---
obs0.19093 24701 91.43 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 27.534 Å2
Baniso -1Baniso -2Baniso -3
1-0.64 Å20 Å20 Å2
2--1.69 Å20 Å2
3----2.33 Å2
Refinement stepCycle: LAST / Resolution: 1.95→61.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2954 0 29 260 3243
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.023062
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.2951.954161
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4135372
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.02623.81139
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.49815487
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.3861517
X-RAY DIFFRACTIONr_chiral_restr0.0830.2448
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022374
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_it3.70121858
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it4.79633004
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it4.21521204
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it5.66431154
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: 1.95→2.001 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.403 84 -
Rwork0.276 1566 -
obs--79.21 %

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