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- PDB-3msl: Fragment Based Discovery and Optimisation of BACE-1 Inhibitors -

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Basic information

Entry
Database: PDB / ID: 3msl
TitleFragment Based Discovery and Optimisation of BACE-1 Inhibitors
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / PROTEASE / ALZHEIMER'S DISEASE / ASPARTIC PROTEASE / ASPARTYL PROTEASE / BASE / BETA-SECRETASE / GLYCOPROTEIN / HYDROLASE / MEMAPSIN 2 / AMYLOID PRECURSOR PROTEIN SECRETASES / ASPARTIC ENDOPEPTIDASES / FRAGMENT-BASED DRUG DESIGN / FLUORESCENCE POLARISATION / 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 / 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
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-EV5 / IODIDE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsSmith, M. / Madden, J. / Barker, J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Fragment-based discovery and optimization of BACE1 inhibitors.
Authors: Madden, J. / Dod, J.R. / Godemann, R. / Kraemer, J. / Smith, M. / Biniszkiewicz, M. / Hallett, D.J. / Barker, J. / Dyekjaer, J.D. / Hesterkamp, T.
History
DepositionApr 29, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 14, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)46,0524
Polymers45,4351
Non-polymers6173
Water2,864159
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)100.190, 100.190, 172.840
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122

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Components

#1: Protein Beta-secretase 1 / / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta-site APP cleaving enzyme 1 / Membrane- ...Beta-site amyloid precursor protein cleaving enzyme 1 / Beta-site APP cleaving enzyme 1 / Membrane-associated aspartic protease 2 / Memapsin-2 / Aspartyl protease 2 / Asp 2 / ASP2


Mass: 45434.957 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 48-453
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE, BACE1, KIAA1149 / Plasmid: PET11A / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-IOD / IODIDE ION / Iodide


Mass: 126.904 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: I
#3: Chemical ChemComp-EV5 / (3S)-3-(2-amino-5-chloro-1H-benzimidazol-1-yl)-N-(cyclohexylmethyl)pentanamide


Mass: 362.897 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H27ClN4O
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 159 / 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: 2.76 Å3/Da / Density % sol: 55.37 %
Crystal growTemperature: 273 K / pH: 6.6
Details: 20% PEG 5000MME 180mM Ammonium Iodide and 180mM Sodium Citrate pH6.6 , VAPOR DIFFUSION, HANGING DROP, temperature 273K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 1.0332
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 17, 2008
RadiationMonochromator: DOUBLE CRYSTAL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 2.4→61.2 Å / Num. obs: 17067 / % possible obs: 86.3 % / Observed criterion σ(I): 2 / Redundancy: 11.89 % / Biso Wilson estimate: 40.5 Å2 / Rmerge(I) obs: 0.102 / Rsym value: 0.106 / Net I/σ(I): 12.9
Reflection shellResolution: 2.4→2.46 Å / Redundancy: 11.7 % / Rmerge(I) obs: 0.287 / Mean I/σ(I) obs: 4.3 / Rsym value: 0.131 / % possible all: 89.5

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Processing

Software
NameVersionClassification
DNAdata collection
PHASERphasing
REFMAC5.5.0102refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1W50

1w50


Resolution: 2.4→50.1 Å / Cor.coef. Fo:Fc: 0.912 / Cor.coef. Fo:Fc free: 0.913 / SU B: 15.199 / SU ML: 0.165 / Cross valid method: THROUGHOUT / σ(F): 2 / ESU R Free: 0.258 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.235 870 4.9 %RANDOM
Rwork0.228 ---
obs0.228 17067 86.4 %-
all-17938 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 24.11 Å2
Baniso -1Baniso -2Baniso -3
1--0.72 Å2-0.36 Å20 Å2
2---0.72 Å20 Å2
3---1.09 Å2
Refinement stepCycle: LAST / Resolution: 2.4→50.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2965 0 27 159 3151
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0223044
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.0361.9544143
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4345375
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.7923.881134
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.72715472
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.171515
X-RAY DIFFRACTIONr_chiral_restr0.0680.2453
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0212329
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_it0.3281.51869
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.5923019
X-RAY DIFFRACTIONr_scbond_it0.18431175
X-RAY DIFFRACTIONr_scangle_it0.3324.51124
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.4→2.46 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.285 56 -
Rwork0.287 1271 -
obs--89.54 %
Refinement TLS params.Method: refined / Origin x: 14.6464 Å / Origin y: -40.8946 Å / Origin z: -0.6597 Å
111213212223313233
T0.0216 Å20.0036 Å2-0.006 Å2-0.0271 Å2-0.0033 Å2--0.0024 Å2
L0.7903 °20.333 °20.4554 °2-0.5553 °20.3606 °2--0.5429 °2
S0.0033 Å °0.052 Å °0.0022 Å °0.0273 Å °0.0064 Å °-0.0065 Å °-0.0005 Å °0.0354 Å °-0.0097 Å °

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