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- PDB-4ke1: Crystal structure of BACE1 in complex with hydroxyethylamine-macr... -

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Basic information

Entry
Database: PDB / ID: 4ke1
TitleCrystal structure of BACE1 in complex with hydroxyethylamine-macrocyclic inhibitor 19
ComponentsBeta-Secretase 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Alzheimer's disease / aspartic protease / amyloid precursor protein (APP) / 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-1R6 / IODIDE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.91 Å
AuthorsWhittington, D.A. / Long, A.M. / Li, V.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Hydroxyethylamine-based inhibitors of BACE1: P1-P3 macrocyclization can improve potency, selectivity, and cell activity.
Authors: Pennington, L.D. / Whittington, D.A. / Bartberger, M.D. / Jordan, S.R. / Monenschein, H. / Nguyen, T.T. / Yang, B.H. / Xue, Q.M. / Vounatsos, F. / Wahl, R.C. / Chen, K. / Wood, S. / Citron, ...Authors: Pennington, L.D. / Whittington, D.A. / Bartberger, M.D. / Jordan, S.R. / Monenschein, H. / Nguyen, T.T. / Yang, B.H. / Xue, Q.M. / Vounatsos, F. / Wahl, R.C. / Chen, K. / Wood, S. / Citron, M. / Patel, V.F. / Hitchcock, S.A. / Zhong, W.
History
DepositionApr 25, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 3, 2013Provider: repository / Type: Initial release
Revision 1.1Jul 17, 2013Group: Database references

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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)46,8516
Polymers45,8221
Non-polymers1,0295
Water4,161231
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)102.480, 102.480, 169.495
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122
Components on special symmetry positions
IDModelComponents
11A-724-

HOH

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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: 45822.445 Da / Num. of mol.: 1 / Fragment: UNP residues 43-453 / Mutation: R56K, R57K
Source method: isolated from a genetically manipulated source
Details: refolded from inclusion bodies / Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149 / Production host: Escherichia coli (E. coli) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: I
#3: Chemical ChemComp-1R6 / (12S)-12-[(1R)-2-{[(4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-yl]amino}-1-hydroxyethyl]-1,13-diazatricyclo[13.3.1.1~6,10~]icosa-6(20),7,9,15(19),16-pentaene-14,18-dione


Mass: 555.707 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H41N3O4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


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


Mass: 18.015 Da / Num. of mol.: 231 / 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: 2.8 Å3/Da / Density % sol: 56.13 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.6
Details: 21% PEG 5000 MME, 0.2 M sodium citrate, 0.2 M ammonium iodide, pH 6.6, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.9793 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Nov 14, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 1.91→28.27 Å / Num. all: 41621 / Num. obs: 41330 / % possible obs: 99.3 % / Redundancy: 14.1 % / Biso Wilson estimate: 28.9 Å2 / Rmerge(I) obs: 0.084 / Net I/σ(I): 16.9

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Processing

Software
NameVersionClassificationNB
SCALA3.2.5data scaling
REFMACrefinement
PDB_EXTRACT3.11data extraction
MOSFLMdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.91→28.27 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.923 / WRfactor Rfree: 0.2624 / WRfactor Rwork: 0.2269 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.8561 / SU B: 6.015 / SU ML: 0.099 / SU R Cruickshank DPI: 0.142 / SU Rfree: 0.1344 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.142 / ESU R Free: 0.134 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2461 2076 5 %RANDOM
Rwork0.2152 ---
obs0.2167 41246 99.66 %-
all-41386 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 183.1 Å2 / Biso mean: 44.5491 Å2 / Biso min: 13.43 Å2
Baniso -1Baniso -2Baniso -3
1--0.09 Å2-0.04 Å20 Å2
2---0.09 Å20 Å2
3---0.13 Å2
Refinement stepCycle: LAST / Resolution: 1.91→28.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2802 0 50 231 3083
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.022926
X-RAY DIFFRACTIONr_bond_other_d0.0010.021984
X-RAY DIFFRACTIONr_angle_refined_deg1.2181.9633975
X-RAY DIFFRACTIONr_angle_other_deg0.8023.0054746
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4595351
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.04623.511131
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.34415459
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.8851517
X-RAY DIFFRACTIONr_chiral_restr0.0690.2430
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0213230
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02623
LS refinement shellResolution: 1.912→1.961 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.363 127 -
Rwork0.348 2505 -
all-2632 -
obs--96.69 %
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)
15.09491.90622.37822.73141.51313.0774-0.1602-0.16820.1717-0.094-0.07040.0969-0.2858-0.13880.23050.20880.0294-0.06390.1542-0.04620.1771.762861.29374.7845
26.42253.44682.33853.90511.78983.0980.4145-0.4248-0.87080.3793-0.1623-0.53780.2327-0.3065-0.25220.1951-0.0095-0.11280.20030.03370.22858.278243.2584-2.6742
34.74294.72281.71756.37351.8573.55110.7786-0.0034-2.34470.84160.164-2.84820.83180.2783-0.94260.37650.0678-0.42120.2702-0.02251.441964.539130.3554-3.451
46.47275.21692.71595.90381.30852.86950.04840.1042-0.93980.09570.1652-0.77330.0962-0.0604-0.21360.15090.0032-0.04710.1835-0.04260.250157.314542.416-7.7335
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A-1 - 147
2X-RAY DIFFRACTION2A148 - 239
3X-RAY DIFFRACTION3A240 - 328
4X-RAY DIFFRACTION4A329 - 385

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