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- PDB-3s2o: Fragment based discovery and optimisation of bace-1 inhibitors -

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Basic information

Entry
Database: PDB / ID: 3s2o
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 / MEMAPSIN 2 / AMYLOID PRECURSOR PROTEIN SECRETASES / ASPARTIC ENDOPEPTIDASES / FRAGMENT-BASED DRUG DESIGN / FLUORESCENCE POLARISATION / TRANSMEMBRANE / 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 / 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-EV6 / IODIDE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsMadden, J. / Godemann, R. / Smith, M.A. / Hallett, D. / Barker, J. / Kraemer, 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
DepositionMay 17, 2011Deposition site: RCSB / Processing site: RCSB
SupersessionJun 1, 2011ID: 3MSM
Revision 1.0Jun 1, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 7, 2011Group: Structure summary
Revision 1.3Sep 13, 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

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Assembly

Deposited unit
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,0904
Polymers45,4351
Non-polymers6553
Water1,24369
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)101.880, 101.880, 170.181
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 / 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: 45434.957 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 46-453
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-EV6 / (3S)-3-(2-amino-5-chloro-1H-benzimidazol-1-yl)-N-[(1R,3S,5R,7R)-tricyclo[3.3.1.1~3,7~]dec-2-yl]pentanamide


Mass: 400.945 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H29ClN4O
#3: Chemical ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: I
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 69 / 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: 2.81 Å3/Da / Density % sol: 56.16 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.4
Details: 22% PEG 5K MME 150MM AMMONIUM IODIDE AND 200MM SODIUM CITRATE PH6.4 , VAPOR DIFFUSION, HANGING DROP, TEMPERATURE 293K

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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: 2.6→61.2 Å / Num. obs: 16771 / % possible obs: 100 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 10.1 % / Biso Wilson estimate: 60.4 Å2 / Rmerge(I) obs: 0.106 / Rsym value: 0.03 / Net I/σ(I): 21.3
Reflection shellResolution: 2.6→2.74 Å / Redundancy: 10.5 % / Mean I/σ(I) obs: 3.8 / Rsym value: 0.168 / % possible all: 100

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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: 2.6→47.72 Å / Cor.coef. Fo:Fc: 0.93 / Cor.coef. Fo:Fc free: 0.88 / SU B: 21.696 / SU ML: 0.222 / Cross valid method: THROUGHOUT / σ(F): 2 / ESU R Free: 0.301 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.261 814 4.9 %RANDOM
Rwork0.205 ---
obs0.208 15902 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 31.52 Å2
Baniso -1Baniso -2Baniso -3
1-0.01 Å20 Å20 Å2
2--0.01 Å20 Å2
3----0.01 Å2
Refinement stepCycle: LAST / Resolution: 2.6→47.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2966 0 30 69 3065
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0223050
X-RAY DIFFRACTIONr_angle_refined_deg1.6691.9564156
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.275375
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.29423.881134
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.41715472
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.7091515
X-RAY DIFFRACTIONr_chiral_restr0.1080.2457
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0212332
X-RAY DIFFRACTIONr_mcbond_it0.7281.51870
X-RAY DIFFRACTIONr_mcangle_it1.34623021
X-RAY DIFFRACTIONr_scbond_it1.91831180
X-RAY DIFFRACTIONr_scangle_it3.1534.51135
LS refinement shellResolution: 2.6→2.67 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.297 53 -
Rwork0.281 1142 -
obs--100 %
Refinement TLS params.Method: refined / Origin x: -14.6555 Å / Origin y: 41.428 Å / Origin z: -0.2475 Å
111213212223313233
T0.0668 Å20.0133 Å20.022 Å2-0.0424 Å20.0155 Å2--0.0475 Å2
L2.8289 °21.5448 °2-1.3888 °2-1.2045 °2-0.7837 °2--1.3971 °2
S-0.0072 Å °-0.0635 Å °0.23 Å °-0.0276 Å °0.0661 Å °0.1785 Å °-0.0094 Å °0.0582 Å °-0.0589 Å °

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