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- PDB-3hw1: Structure of Bace (beta secretase) in complex with ligand EV2 -

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Basic information

Entry
Database: PDB / ID: 3hw1
TitleStructure of Bace (beta secretase) in complex with ligand EV2
ComponentsBeta-secretase 1
KeywordsHYDROLASE / 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 / Disulfide bond / Transmembrane / Zymogen
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
3-pyrrolidin-1-ylquinoxalin-2-amine / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.48 Å
AuthorsGodemann, R. / Madden, J. / Kramer, J. / Smith, M.A. / Barker, J. / Ebneth, A.
CitationJournal: Biochemistry / Year: 2009
Title: Fragment-Based Discovery of BACE1 Inhibitors Using Functional Assays
Authors: Godemann, R. / Madden, J. / Kramer, J. / Smith, M.A. / Fritz, U. / Hesterkamp, T. / Barker, J. / Hoeppner, S. / Hallett, D. / Cesura, A. / Ebneth, A. / Kemp, J.
History
DepositionJun 17, 2009Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Nov 3, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Refinement description / Version format compliance
Revision 1.2Nov 10, 2021Group: Database references / Derived calculations / Category: database_2 / 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
Revision 1.3Nov 1, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)138,1187
Polymers137,3833
Non-polymers7354
Water2,108117
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,0092
Polymers45,7941
Non-polymers2141
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,0092
Polymers45,7941
Non-polymers2141
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,1013
Polymers45,7941
Non-polymers3062
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)230.625, 99.880, 62.900
Angle α, β, γ (deg.)90.00, 103.12, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Beta-secretase 1 / / BBACE1 / eta-site amyloid precursor protein cleaving enzyme 1 / Beta-site APP cleaving enzyme 1 / ...BBACE1 / eta-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 46-453 / Mutation: R(-5)K, R(-4)T
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-EV2 / 3-pyrrolidin-1-ylquinoxalin-2-amine


Mass: 214.266 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C12H14N4
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 117 / 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: 2.57 Å3/Da / Density % sol: 52.1 %
Crystal growTemperature: 295 K / Method: vapor diffusion / pH: 6
Details: 10% PEG 4000, 100mM MES pH 6.0, VAPOR DIFFUSION, temperature 295K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 0.9999 Å
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: 0.9999 Å / Relative weight: 1
ReflectionResolution: 2.48→48.8 Å / Num. all: 47564 / Num. obs: 48552 / % possible obs: 98.3 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 3.3 % / Biso Wilson estimate: 20.736 Å2 / Rmerge(I) obs: 0.047 / Rsym value: 0.047 / Net I/σ(I): 14.82
Reflection shellResolution: 2.48→2.57 Å / Redundancy: 3.2 % / Rmerge(I) obs: 0.657 / Mean I/σ(I) obs: 3.01 / Num. unique all: 4849 / Rsym value: 0.657 / % possible all: 96.2

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Processing

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

2b8l


Resolution: 2.48→48.8 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.902 / SU B: 32.348 / SU ML: 0.325 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 2 / σ(I): 2 / ESU R: 0.492 / ESU R Free: 0.305 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28115 986 2 %RANDOM
Rwork0.22585 ---
all0.22703 48570 --
obs0.226 47564 100 %-
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: 20.736 Å2
Baniso -1Baniso -2Baniso -3
1--7.7 Å20 Å2-0.13 Å2
2---5.13 Å20 Å2
3---12.77 Å2
Refinement stepCycle: LAST / Resolution: 2.48→48.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8784 0 54 117 8955
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0229073
X-RAY DIFFRACTIONr_bond_other_d0.0010.028048
X-RAY DIFFRACTIONr_angle_refined_deg1.211.95512327
X-RAY DIFFRACTIONr_angle_other_deg1.17318674
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.72751107
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.66323.771411
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.73151423
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.2261551
X-RAY DIFFRACTIONr_chiral_restr0.0710.21335
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0210118
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021940
X-RAY DIFFRACTIONr_nbd_refined0.1890.21704
X-RAY DIFFRACTIONr_nbd_other0.1920.27984
X-RAY DIFFRACTIONr_nbtor_refined0.1830.24366
X-RAY DIFFRACTIONr_nbtor_other0.0830.24990
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1560.2257
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.0040.21
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1910.239
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2810.258
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1040.29
X-RAY DIFFRACTIONr_mcbond_it0.86927126
X-RAY DIFFRACTIONr_mcbond_other0.09322291
X-RAY DIFFRACTIONr_mcangle_it1.07538935
X-RAY DIFFRACTIONr_scbond_it1.4544304
X-RAY DIFFRACTIONr_scangle_it2.14563391
LS refinement shellResolution: 2.48→2.544 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.474 70 -
Rwork0.51 3388 -
obs--100 %
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)
111.3461-2.46372.759512.9113-1.70936.46460.26581.11310.5961-2.19840.0638-0.7897-0.39650.7364-0.32950.5385-0.20310.27690.2938-0.0955-0.1045-20.693-85.977-8.407
22.80342.74250.33136.16612.61093.0124-0.20630.2365-0.1299-0.44990.4846-1.0037-0.21430.6313-0.27820.0721-0.02780.13830.1563-0.1199-0.0232-15.699-78.7917.118
37.8327-16.4819-2.45735.36013.1716.6613-0.25170.0581-1.39171.14580.5411-1.04510.8740.7128-0.28950.10490.0351-0.06870.2337-0.2390.4284-12.58-82.49819.602
41.78090.04020.66174.78341.10481.71240.12730.0694-0.49410.22640.109-0.49880.12890.2457-0.23640.04580.0149-0.00090.0857-0.073-0.1793-26.744-103.922.221
57.7786-10.285.625417.9087-7.534710.01010.55140.0686-0.8685-0.1033-0.24470.89720.07670.1387-0.3066-0.05170.0002-0.00850.1261-0.1346-0.1287-73.155-22.5540.81
63.28420.6048-0.42473.20171.40151.89320.26230.7291-1.1927-0.5845-0.20920.70870.3892-0.2608-0.05310.41080.1635-0.2160.4098-0.34690.3693-72.464-38.03830.485
75.769-7.4517-0.016922.2569-15.506619.08961.00720.8765-0.46590.1108-0.95570.9275-0.57070.9236-0.05160.6330.0397-0.06780.5878-0.39830.6518-65.536-47.54325.95
82.9374-0.44941.32682.35890.54012.3960.24810.4973-0.4885-0.12810.0291-0.37560.24190.299-0.27710.0410.10030.0060.1148-0.16560.0125-52.259-25.59744.739
98.1999-6.01152.452430.5728-7.22335.4478-0.06750.49570.3091-0.5689-0.1085-0.34870.04520.27050.1761-0.0705-0.04310.01010.04580.0049-0.4827-27.012-61.40813.943
106.20981.59270.9351.79430.05412.3045-0.10460.08520.6663-0.11630.09630.2941-0.0847-0.05760.00820.0032-0.0350.0285-0.0598-0.0093-0.2025-44.533-56.66514.761
1138.783126.98922.357518.82372.07014.54660.4668-0.95323.25441.0642-0.80221.534-0.65260.08510.33540.18880.06650.01920.1148-0.17120.5988-52.302-46.50819.54
124.1220.83230.88742.91760.32071.0706-0.1695-0.26781.13350.1573-0.08550.1583-0.2259-0.10950.2550.01890.0257-0.02280.048-0.08340.0303-22.11-46.42728.068
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 11
2X-RAY DIFFRACTION1A-3 - 0
3X-RAY DIFFRACTION2A12 - 63
4X-RAY DIFFRACTION2A81 - 146
5X-RAY DIFFRACTION3A64 - 80
6X-RAY DIFFRACTION4A147 - 385
7X-RAY DIFFRACTION5B1 - 11
8X-RAY DIFFRACTION5B-4 - 0
9X-RAY DIFFRACTION6B12 - 63
10X-RAY DIFFRACTION6B81 - 146
11X-RAY DIFFRACTION7B64 - 80
12X-RAY DIFFRACTION8B147 - 385
13X-RAY DIFFRACTION9C1 - 11
14X-RAY DIFFRACTION9C-4 - 0
15X-RAY DIFFRACTION10C12 - 63
16X-RAY DIFFRACTION10C81 - 146
17X-RAY DIFFRACTION11C64 - 80
18X-RAY DIFFRACTION12C147 - 385

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