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- PDB-3msj: Structure of bace (beta secretase) in complex with inhibitor -

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Basic information

Entry
Database: PDB / ID: 3msj
TitleStructure of bace (beta secretase) in complex with inhibitor
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 / 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-EV3 / Beta-secretase 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsMadden, J. / Kramer, J. / Smith, M.A. / Barker, J. / Godemann, R.
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
B: BETA-SECRETASE 1
C: BETA-SECRETASE 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)139,62623
Polymers137,3833
Non-polymers2,24320
Water11,638646
1
A: BETA-SECRETASE 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,6659
Polymers45,7941
Non-polymers8708
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: BETA-SECRETASE 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,75710
Polymers45,7941
Non-polymers9629
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: BETA-SECRETASE 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,2044
Polymers45,7941
Non-polymers4103
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)229.196, 98.829, 63.132
Angle α, β, γ (deg.)90.00, 103.36, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein BETA-SECRETASE 1 / / BACE1 / BETA-SITE AMYLOID PRECURSOR PROTEIN CLEAVING ENZYME 1 / BETA-SITE APP CLEAVING ENZYME 1 / ...BACE1 / 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: 45794.371 Da / Num. of mol.: 3 / Fragment: UNP RESIDUES 43-453
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Gene: BACE1 / Plasmid: PET11A / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21 (DE3) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-EV3 / 3-(2-amino-5-chloro-1H-benzimidazol-1-yl)propan-1-ol


Mass: 225.675 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C10H12ClN3O
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 17 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 646 / 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: 2.53 Å3/Da / Density % sol: 51.42 %
Crystal growTemperature: 273 K / Method: vapor diffusion / pH: 6
Details: 10% PEG 4000, 100MM MES PH 6.0, VAPOR DIFFUSION, TEMPERATURE 273K, temperature 273 KK

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jan 15, 2008
RadiationMonochromator: DOUBLE CRYSTAL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→111.8 Å / Num. obs: 126584 / % possible obs: 94.7 % / Observed criterion σ(I): 0 / Redundancy: 2.2 % / Rmerge(I) obs: 0.053 / Net I/σ(I): 7.2
Reflection shellResolution: 1.8→1.9 Å / Redundancy: 2.2 % / Rmerge(I) obs: 0.678 / Mean I/σ(I) obs: 1 / % possible all: 94.2

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Processing

Software
NameVersionClassification
XDSdata scaling
PHASERphasing
REFMAC5.2.0005refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2B8L

2b8l


Resolution: 1.8→111.8 Å / Cor.coef. Fo:Fc: 0.971 / Cor.coef. Fo:Fc free: 0.96 / SU B: 7.581 / SU ML: 0.11 / Cross valid method: THROUGHOUT / ESU R Free: 0.11 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20846 1212 1 %RANDOM
Rwork0.17718 ---
obs0.1775 118247 94.37 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 16.593 Å2
Baniso -1Baniso -2Baniso -3
1--1.96 Å20 Å2-0.86 Å2
2---1.33 Å20 Å2
3---2.89 Å2
Refinement stepCycle: LAST / Resolution: 1.8→111.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8824 0 147 646 9617
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0229288
X-RAY DIFFRACTIONr_bond_other_d0.0020.028239
X-RAY DIFFRACTIONr_angle_refined_deg1.3531.95812615
X-RAY DIFFRACTIONr_angle_other_deg0.743319160
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.83351140
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.823.835425
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.639151465
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.9971552
X-RAY DIFFRACTIONr_chiral_restr0.0750.21352
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0210334
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021968
X-RAY DIFFRACTIONr_nbd_refined0.190.21912
X-RAY DIFFRACTIONr_nbd_other0.1930.29400
X-RAY DIFFRACTIONr_nbtor_refined0.1860.24648
X-RAY DIFFRACTIONr_nbtor_other0.0880.25297
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1480.2704
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.3180.237
X-RAY DIFFRACTIONr_symmetry_vdw_other0.260.2107
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1310.235
X-RAY DIFFRACTIONr_mcbond_it2.13427112
X-RAY DIFFRACTIONr_mcbond_other0.55422310
X-RAY DIFFRACTIONr_mcangle_it2.58939080
X-RAY DIFFRACTIONr_scbond_it3.9444427
X-RAY DIFFRACTIONr_scangle_it5.17763524
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.376 91 -
Rwork0.323 8371 -
obs--91.27 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
18.2609-5.7152.894216.1508-2.08653.35290.16920.3660.0189-0.2930.0057-0.39440.07320.2377-0.1749-0.1985-0.01880.0804-0.1904-0.0711-0.3124-26.992-60.70214.044
25.49720.91271.20361.45090.16081.7678-0.0344-0.06980.3813-0.12520.01570.08310.0178-0.03160.0186-0.2004-0.04510.0268-0.2363-0.0331-0.2371-44.371-55.95714.761
326.251223.59192.308432.2339-0.56845.88480.4529-0.85651.55281.0278-0.5740.4565-0.70540.08370.1211-0.10320.01750.0315-0.1432-0.16960.0306-51.725-45.66519.375
46.52691.11831.73232.38980.28341.2588-0.2128-0.41521.29660.0827-0.13220.0635-0.0969-0.18710.3451-0.21760.0283-0.0277-0.1808-0.1274-0.0147-22.19-46.04728.054
512.8531-3.28692.252112.5745-3.11526.70190.2041.26860.2548-1.92110.2613-0.0388-0.13170.3133-0.46540.3736-0.21710.24180.0508-0.1087-0.2086-20.432-85.349-7.929
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1B1 - 11
2X-RAY DIFFRACTION1A44 - 48
3X-RAY DIFFRACTION2B12 - 63
4X-RAY DIFFRACTION2B81 - 146
5X-RAY DIFFRACTION3B64 - 80
6X-RAY DIFFRACTION4B147 - 385
8X-RAY DIFFRACTION5C45 - 48

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