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- PDB-4dju: Structure of BACE Bound to 2-imino-3-methyl-5,5-diphenylimidazoli... -

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Basic information

Entry
Database: PDB / ID: 4dju
TitleStructure of BACE Bound to 2-imino-3-methyl-5,5-diphenylimidazolidin-4-one
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / BACE1 / Alzheimers / 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-0KK / L(+)-TARTARIC ACID / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsStrickland, C. / Cumming, J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Structure based design of iminohydantoin BACE1 inhibitors: Identification of an orally available, centrally active BACE1 inhibitor.
Authors: Cumming, J.N. / Smith, E.M. / Wang, L. / Misiaszek, J. / Durkin, J. / Pan, J. / Iserloh, U. / Wu, Y. / Zhu, Z. / Strickland, C. / Voigt, J. / Chen, X. / Kennedy, M.E. / Kuvelkar, R. / Hyde, ...Authors: Cumming, J.N. / Smith, E.M. / Wang, L. / Misiaszek, J. / Durkin, J. / Pan, J. / Iserloh, U. / Wu, Y. / Zhu, Z. / Strickland, C. / Voigt, J. / Chen, X. / Kennedy, M.E. / Kuvelkar, R. / Hyde, L.A. / Cox, K. / Favreau, L. / Czarniecki, M.F. / Greenlee, W.J. / McKittrick, B.A. / Parker, E.M. / Stamford, A.W.
History
DepositionFeb 2, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 21, 2012Provider: repository / Type: Initial release
Revision 1.1Apr 4, 2012Group: Database references
Revision 1.2Nov 6, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)93,3316
Polymers92,5002
Non-polymers8314
Water16,141896
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,6653
Polymers46,2501
Non-polymers4152
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,6653
Polymers46,2501
Non-polymers4152
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)86.291, 89.139, 131.213
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: BACE, BACE1, KIAA1149 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-0KK / (2E)-2-imino-3-methyl-5,5-diphenylimidazolidin-4-one


Mass: 265.310 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H15N3O
#3: Chemical ChemComp-TLA / L(+)-TARTARIC ACID


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


Mass: 18.015 Da / Num. of mol.: 896 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.73 Å3/Da / Density % sol: 54.91 %
Crystal growTemperature: 277 K / Method: hanging drop / Details: Hanging Drop, temperature 277K

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Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.8→20 Å / Num. obs: 94197 / % possible obs: 100 % / Rmerge(I) obs: 0.089 / Χ2: 1.071 / Net I/σ(I): 10.2
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
1.8-1.830.49746291.0551100
1.83-1.860.43946241.0711100
1.86-1.90.3947031.1051100
1.9-1.940.31246621.1411100
1.94-1.980.24846561.1051100
1.98-2.030.21446651.0781100
2.03-2.080.18746541.1521100
2.08-2.130.16646651.0951100
2.13-2.20.1546681.0991100
2.2-2.270.13646921.1251100
2.27-2.350.12947021.0821100
2.35-2.440.11946851.0741100
2.44-2.550.1146831.0591100
2.55-2.690.09647231.0411100
2.69-2.860.08747131.0091100
2.86-3.070.07747421.071100
3.07-3.380.06747221.003199.9
3.38-3.870.05848011.0431100
3.87-4.860.05448061.026199.9
4.86-200.05250020.998199.6

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
BUSTER-TNTrefinement
PDB_EXTRACT3.1data extraction
CrystalCleardata collection
DENZOdata reduction
CNSphasing
BUSTER2.11.2refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→19.86 Å / Cor.coef. Fo:Fc: 0.9556 / Cor.coef. Fo:Fc free: 0.9462 / Occupancy max: 1 / Occupancy min: 1 / SU R Cruickshank DPI: 0.109 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2071 4726 5.02 %RANDOM
Rwork0.1855 ---
obs0.1866 94127 99.95 %-
Displacement parametersBiso max: 93.45 Å2 / Biso mean: 22.8194 Å2 / Biso min: 8.71 Å2
Baniso -1Baniso -2Baniso -3
1-2.8987 Å20 Å20 Å2
2---3.8055 Å20 Å2
3---0.9068 Å2
Refine analyzeLuzzati coordinate error obs: 0.201 Å
Refinement stepCycle: LAST / Resolution: 1.8→19.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6112 0 60 896 7068
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2117SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes148HARMONIC2
X-RAY DIFFRACTIONt_gen_planes965HARMONIC5
X-RAY DIFFRACTIONt_it6336HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion808SEMIHARMONIC5
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_contact8118SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d6336HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg8623HARMONIC21.01
X-RAY DIFFRACTIONt_omega_torsion4
X-RAY DIFFRACTIONt_other_torsion13.99
LS refinement shellResolution: 1.8→1.85 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2636 362 5.29 %
Rwork0.215 6486 -
all0.2176 6848 -
obs--99.95 %
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)
10.44440.20990.39460.22940.29490.4165-0.00060.00060.0062-0.0104-0.02420.0267-0.0203-0.03050.0248-0.0175-0.0004-0.007-0.0046-0.0148-0.013627.97935.50527.8256
20.50890.1517-0.43860.1626-0.23530.3852-0.00130.0002-0.0008-0.0048-0.0116-0.00910.00540.02080.0129-0.0163-0.0020.00550.00390.0063-0.021215.102739.516862.3489
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A58 - 447
2X-RAY DIFFRACTION2{ B|* }B58 - 446

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