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- PDB-4r8y: BACE-1 in complex with (R)-4-(2-cyclohexylethyl)-4-(((R)-1-(2-cyc... -

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Basic information

Entry
Database: PDB / ID: 4r8y
TitleBACE-1 in complex with (R)-4-(2-cyclohexylethyl)-4-(((R)-1-(2-cyclopentylacetyl)pyrrolidin-3-yl)methyl)-1-methyl-5-oxoimidazolidin-2-iminium
ComponentsBeta-secretase 1
KeywordsHydrolase/Hydrolase Inhibitor / Aspartyl protease / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta-site APP cleaving enzyme 1 / 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-3KO / L(+)-TARTARIC ACID / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.9 Å
AuthorsOrth, P. / Caldwell, J.P. / Strickland, C.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2014
Title: Discovery of potent iminoheterocycle BACE1 inhibitors.
Authors: Caldwell, J.P. / Mazzola, R.D. / Durkin, J. / Chen, J. / Chen, X. / Favreau, L. / Kennedy, M. / Kuvelkar, R. / Lee, J. / McHugh, N. / McKittrick, B. / Orth, P. / Stamford, A. / Strickland, C. ...Authors: Caldwell, J.P. / Mazzola, R.D. / Durkin, J. / Chen, J. / Chen, X. / Favreau, L. / Kennedy, M. / Kuvelkar, R. / Lee, J. / McHugh, N. / McKittrick, B. / Orth, P. / Stamford, A. / Strickland, C. / Voigt, J. / Wang, L. / Zhang, L. / Zhang, Q. / Zhu, Z.
History
DepositionSep 3, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 5, 2014Provider: repository / Type: Initial release
Revision 1.1Dec 17, 2014Group: 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
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)93,4835
Polymers92,5002
Non-polymers9833
Water15,403855
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,6672
Polymers46,2501
Non-polymers4171
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,8173
Polymers46,2501
Non-polymers5672
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)86.400, 89.430, 131.000
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 / 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: 46249.926 Da / Num. of mol.: 2 / Fragment: UNP residues 41-454
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-3KO / (2E,5R)-5-(2-cyclohexylethyl)-5-{[(3R)-1-(cyclopentylacetyl)pyrrolidin-3-yl]methyl}-2-imino-3-methylimidazolidin-4-one


Mass: 416.600 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H40N4O2
#3: Chemical ChemComp-TLA / L(+)-TARTARIC ACID / Tartaric acid


Mass: 150.087 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H6O6
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 855 / 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: 2.74 Å3/Da / Density % sol: 55.04 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Oct 13, 2004
RadiationMonochromator: mirror / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→20 Å / Num. all: 80504 / Num. obs: 77043 / % possible obs: 95.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Rmerge(I) obs: 0.084 / Χ2: 1.001 / Net I/σ(I): 10.2
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
1.9-1.930.41939561199.4
1.93-1.970.34839501.004199.3
1.97-2.010.29739741.002199.2
2.01-2.050.25739131.005199.2
2.05-2.090.23239471.002198.9
2.09-2.140.20639161198.6
2.14-2.190.18339041198.2
2.19-2.250.16439051198
2.25-2.320.15139161197.5
2.32-2.390.14238741197
2.39-2.480.12938671196.6
2.48-2.580.11238691196.5
2.58-2.690.10138431195.3
2.69-2.840.09438111195.2
2.84-3.010.0838071194.4
3.01-3.250.07337781193.6
3.25-3.570.06437531192.2
3.57-4.080.05837101190.9
4.08-5.130.05236791189.1
5.13-200.04536711185.3

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Processing

Software
NameVersionClassificationNB
BUSTER-TNTrefinement
SCALEPACKdata scaling
PDB_EXTRACT3.1data extraction
ADSCQuantumdata collection
DENZOdata reduction
CNSphasing
BUSTER2.11.4refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.9→19.9 Å / Cor.coef. Fo:Fc: 0.9561 / Cor.coef. Fo:Fc free: 0.9445 / Occupancy max: 1 / Occupancy min: 1 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2051 3862 5.02 %RANDOM
Rwork0.1741 ---
obs0.1757 76983 95.64 %-
all-80504 --
Displacement parametersBiso max: 122.84 Å2 / Biso mean: 22.8137 Å2 / Biso min: 9.77 Å2
Baniso -1Baniso -2Baniso -3
1-4.7032 Å20 Å20 Å2
2---5.7775 Å20 Å2
3---1.0743 Å2
Refine analyzeLuzzati coordinate error obs: 0.185 Å
Refinement stepCycle: LAST / Resolution: 1.9→19.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6039 0 70 855 6964
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2068SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes144HARMONIC2
X-RAY DIFFRACTIONt_gen_planes916HARMONIC5
X-RAY DIFFRACTIONt_it6273HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion799SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact7980SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d6273HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg8540HARMONIC21.06
X-RAY DIFFRACTIONt_omega_torsion4.24
X-RAY DIFFRACTIONt_other_torsion14.95
LS refinement shellResolution: 1.9→1.95 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2363 270 4.63 %
Rwork0.1885 5557 -
all0.1907 5827 -
obs--95.64 %

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