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- PDB-4r92: BACE-1 in complex with (R)-4-(2-cyclohexylethyl)-4-(((1S,3R)-3-(i... -

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Basic information

Entry
Database: PDB / ID: 4r92
TitleBACE-1 in complex with (R)-4-(2-cyclohexylethyl)-4-(((1S,3R)-3-(isonicotinamido)cyclohexyl)methyl)-1-methyl-5-oxoimidazolidin-2-iminium
ComponentsBeta-secretase 1
KeywordsHydrolase/Hydrolase inhibitor / Aspartic Protease / 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 / 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
Chem-3KU / L(+)-TARTARIC ACID / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.71 Å
AuthorsOrth, P. / Strickland, C. / Caldwell, J.P.
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)93,6796
Polymers92,5002
Non-polymers1,1794
Water14,880826
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,6902
Polymers46,2501
Non-polymers4401
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,9904
Polymers46,2501
Non-polymers7403
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)86.680, 89.460, 131.030
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-3KU / N-[(1R,3S)-3-{[(2E,4R)-4-(2-cyclohexylethyl)-2-imino-1-methyl-5-oxoimidazolidin-4-yl]methyl}cyclohexyl]pyridine-4-carboxamide


Mass: 439.594 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H37N5O2
#3: Chemical ChemComp-TLA / L(+)-TARTARIC ACID / Tartaric acid


Mass: 150.087 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H6O6
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 826 / 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: 2.75 Å3/Da / Density % sol: 55.21 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 20% PEG 3350, 200mM K/Na tatrate, 100mM Hepes, pH 7.0, vapor diffusion, hanging drop, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.54178 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Details: mirror
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.71→20 Å / Num. obs: 107305 / % possible obs: 97.1 % / Redundancy: 5.1 % / Rmerge(I) obs: 0.075 / Χ2: 1 / Net I/σ(I): 11.4
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
1.71-1.745.10.46854470.9991100
1.74-1.775.10.39654631.0051100
1.77-1.815.10.33854791.0021100
1.81-1.845.10.28454441.0011100
1.84-1.885.10.265546311100
1.88-1.934.60.21654811199.8
1.93-1.975.20.192546511100
1.97-2.035.20.153546411100
2.03-2.095.20.134550711100
2.09-2.155.20.123548311100
2.15-2.234.40.11653740.999197.7
2.23-2.324.90.10554831199.9
2.32-2.435.30.092551911100
2.43-2.555.30.083553511100
2.55-2.715.30.071553711100
2.71-2.925.30.063551511100
2.92-3.215.30.057558311100
3.21-3.684.90.05140801172.9
3.68-4.624.60.04241331.001173.2
4.62-205.10.0458501.001199.8

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Processing

Software
NameVersionClassificationNB
BUSTER-TNTrefinement
SCALEPACKdata scaling
PDB_EXTRACT3.1data extraction
CrystalCleardata collection
DENZOdata reduction
CNSphasing
BUSTER2.11.4refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.71→19.91 Å / Cor.coef. Fo:Fc: 0.9546 / Cor.coef. Fo:Fc free: 0.9436 / Occupancy max: 1 / Occupancy min: 1 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2166 5361 5 %RANDOM
Rwork0.1923 ---
obs0.1935 107207 97.11 %-
Displacement parametersBiso max: 110.63 Å2 / Biso mean: 21.7351 Å2 / Biso min: 9.42 Å2
Baniso -1Baniso -2Baniso -3
1-3.0753 Å20 Å20 Å2
2---4.5377 Å20 Å2
3---1.4624 Å2
Refine analyzeLuzzati coordinate error obs: 0.193 Å
Refinement stepCycle: LAST / Resolution: 1.71→19.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6037 0 84 826 6947
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2066SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes147HARMONIC2
X-RAY DIFFRACTIONt_gen_planes923HARMONIC5
X-RAY DIFFRACTIONt_it6284HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion801SEMIHARMONIC5
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_contact7937SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d6284HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg8554HARMONIC21.05
X-RAY DIFFRACTIONt_omega_torsion4.35
X-RAY DIFFRACTIONt_other_torsion14.59
LS refinement shellResolution: 1.71→1.75 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2638 419 5.19 %
Rwork0.2254 7662 -
all0.2273 8081 -
obs--97.11 %

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