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- PDB-5hu0: BACE1 in complex with 4-(3-(furan-2-carboxamido)phenyl)-1-methyl-... -

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Basic information

Entry
Database: PDB / ID: 5hu0
TitleBACE1 in complex with 4-(3-(furan-2-carboxamido)phenyl)-1-methyl-5-oxo-4-phenylimidazolidin-2-iminium
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / ALZHEIMER'S / ASPARTYL PROTEASE / HYDROLASE / 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-66H / L(+)-TARTARIC ACID / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Resolution: 1.83 Å
AuthorsOrth, P.
CitationJournal: J. Med. Chem. / Year: 2016
Title: Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)-A beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer's Disease.
Authors: Scott, J.D. / Li, S.W. / Brunskill, A.P. / Chen, X. / Cox, K. / Cumming, J.N. / Forman, M. / Gilbert, E.J. / Hodgson, R.A. / Hyde, L.A. / Jiang, Q. / Iserloh, U. / Kazakevich, I. / Kuvelkar, ...Authors: Scott, J.D. / Li, S.W. / Brunskill, A.P. / Chen, X. / Cox, K. / Cumming, J.N. / Forman, M. / Gilbert, E.J. / Hodgson, R.A. / Hyde, L.A. / Jiang, Q. / Iserloh, U. / Kazakevich, I. / Kuvelkar, R. / Mei, H. / Meredith, J. / Misiaszek, J. / Orth, P. / Rossiter, L.M. / Slater, M. / Stone, J. / Strickland, C.O. / Voigt, J.H. / Wang, G. / Wang, H. / Wu, Y. / Greenlee, W.J. / Parker, E.M. / Kennedy, M.E. / Stamford, A.W.
History
DepositionJan 27, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 9, 2016Provider: repository / Type: Initial release
Revision 1.1Nov 30, 2016Group: Database references
Revision 1.2Jan 4, 2017Group: Database references

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)93,0086
Polymers91,9592
Non-polymers1,0494
Water16,664925
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,5043
Polymers45,9801
Non-polymers5242
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,5043
Polymers45,9801
Non-polymers5242
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)86.475, 89.822, 131.134
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 45979.578 Da / Num. of mol.: 2 / Fragment: UNP residues 43-454
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149 / Production host: Escherichia coli (E. coli) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-TLA / L(+)-TARTARIC ACID / Tartaric acid


Mass: 150.087 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H6O6
#3: Chemical ChemComp-66H / N-{3-[(2E,4R)-2-imino-1-methyl-5-oxo-4-phenylimidazolidin-4-yl]phenyl}furan-2-carboxamide


Mass: 374.393 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H18N4O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 925 / 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: 2.94 Å3/Da / Density % sol: 58.1 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 15% PEG 3350, 200MM NA/K TARTRATE, 100MM HEPES PH7

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E DW / Wavelength: 1.54178 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Feb 22, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.83→20 Å / Num. obs: 88997 / % possible obs: 98.2 % / Redundancy: 4.1 % / Rmerge(I) obs: 0.114 / Χ2: 1.007 / Net I/av σ(I): 11.379 / Net I/σ(I): 5.5 / Num. measured all: 361899
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
1.83-1.863.80.52.7196.1
1.86-1.93.70.4662.9196.2
1.9-1.933.70.4173.1196.1
1.93-1.973.70.3673.3196.6
1.97-2.013.70.3383.5196.7
2.01-2.063.90.3093.8197.1
2.06-2.113.90.2754.2197.6
2.11-2.1740.2634.4197.6
2.17-2.234.10.2315198.2
2.23-2.314.10.2125.6198.3
2.31-2.394.10.1946.2198.6
2.39-2.484.20.1846.5198.8
2.48-2.64.20.1597.2199.1
2.6-2.734.20.1358.5199.1
2.73-2.94.20.10910.2199.4
2.9-3.134.20.08811.8199.4
3.13-3.444.40.06715.3199.8
3.44-3.934.50.04721.7199.9
3.93-4.944.50.03825.91100
4.94-204.30.03825.2199.9

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
PDB_EXTRACT3.1data extraction
DENZOdata reduction
BUSTER2.11.6refinement
AMoREphasing
RefinementResolution: 1.83→19.97 Å / Cor.coef. Fo:Fc: 0.9542 / Cor.coef. Fo:Fc free: 0.9408 / Occupancy max: 1 / Occupancy min: 1 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.1985 3589 4.04 %RANDOM
Rwork0.169 84480 --
obs0.1702 88928 98.25 %-
Displacement parametersBiso max: 105.54 Å2 / Biso mean: 17.5195 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1-2.5385 Å20 Å20 Å2
2---3.2333 Å20 Å2
3---0.6948 Å2
Refine analyzeLuzzati coordinate error obs: 0.226 Å
Refinement stepCycle: LAST / Resolution: 1.83→19.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6108 0 76 925 7109
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.006
X-RAY DIFFRACTIONc_angle_d1.464
LS refinement shellResolution: 1.83→1.88 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2445 237 3.73 %
Rwork0.2102 6120 -
all0.2114 6357 -
obs--95.9 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1MSI_CNX_TOPPAR:protein_rep.paramMSI_CNX_TOPPAR:protein.top
X-RAY DIFFRACTION2MSI_CNX_TOPPAR:water_rep.paramMSI_CNX_TOPPAR:water.top
X-RAY DIFFRACTION3MSI_CNX_TOPPAR:ion.paramMSI_CNX_TOPPAR:ion.top
X-RAY DIFFRACTION4paratartrate.protoptartrate.pro
X-RAY DIFFRACTION5parasch777715.protopsch777715.pro

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