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- PDB-3udq: Crystal Structure of BACE with Compound 13 -

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Basic information

Entry
Database: PDB / ID: 3udq
TitleCrystal Structure of BACE with Compound 13
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / 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 / protein serine/threonine kinase binding / 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 / late endosome / synaptic vesicle / peptidase activity / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / aspartic-type endopeptidase activity / lysosome / 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-09E / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / RIGID BODY REFINEMENT / Resolution: 2.73 Å
AuthorsEfremov, I.V. / Vajdos, F.F. / Borzilleri, K. / Capetta, S. / Dorff, P. / Dutra, J. / Mansour, M. / Oborski, C. / O'Connell, T. / O'Sullivan, T.J. ...Efremov, I.V. / Vajdos, F.F. / Borzilleri, K. / Capetta, S. / Dorff, P. / Dutra, J. / Mansour, M. / Oborski, C. / O'Connell, T. / O'Sullivan, T.J. / Pandit, J. / Wang, H. / Withka, J.
Citation
Journal: J.Med.Chem. / Year: 2012
Title: Discovery and optimization of a novel spiropyrrolidine inhibitor of {beta}-secretase (BACE1) through fragment-based drug design.
Authors: Efremov, I.V. / Vajdos, F.F. / Borzilleri, K.A. / Capetta, S. / Chen, H. / Dorff, P.H. / Dutra, J.K. / Goldstein, S.W. / Mansour, M. / McColl, A. / Noell, S. / Oborski, C.E. / O'Connell, T.N. ...Authors: Efremov, I.V. / Vajdos, F.F. / Borzilleri, K.A. / Capetta, S. / Chen, H. / Dorff, P.H. / Dutra, J.K. / Goldstein, S.W. / Mansour, M. / McColl, A. / Noell, S. / Oborski, C.E. / O'Connell, T.N. / O'Sullivan, T.J. / Pandit, J. / Wang, H. / Wei, B. / Withka, J.M.
#1: Journal: Protein Pept.Lett. / Year: 2008
Title: High yield expression of human BACE constructs in Escherichia coli for refolding, purification, and high resolution diffracting crystal forms.
Authors: Tomasselli, A.G. / Paddock, D.J. / Emmons, T.L. / Mildner, A.M. / Leone, J.W. / Lull, J.M. / Cialdella, J.I. / Prince, D.B. / Fischer, H.D. / Heinrikson, R.L. / Benson, T.E.
History
DepositionOct 28, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 18, 2012Provider: repository / Type: Initial release
Revision 1.1Jun 19, 2013Group: Database references
Revision 1.2Apr 4, 2018Group: Data collection / Refinement description / Category: diffrn_source / software / Item: _diffrn_source.type / _software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,6482
Polymers45,1571
Non-polymers4911
Water2,144119
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)74.467, 103.824, 100.052
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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Components

#1: Protein Beta-secretase 1 / BACE / Aspartyl protease 2 / ASP2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 / ...BACE / 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: 45156.730 Da / Num. of mol.: 1 / Fragment: UNP residues 58-453
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-09E / (4S)-6-bromo-1,1-dioxido-3,4-dihydro-2H-thiochromen-4-yl (3S,5'R)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylate


Mass: 491.355 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H19BrN2O5S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 119 / 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: 2.14 Å3/Da / Density % sol: 42.56 %
Crystal growTemperature: 298 K / Method: vapor diffusion
Details: protein in sodium borate, pH 8.5, reservoir: 30% PEG200, 0.1 M sodium acetate, pH 5.2-5.4, VAPOR DIFFUSION, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E / Wavelength: 1.5418 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Apr 8, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.729→100.052 Å / Num. all: 10639 / Num. obs: 10639 / % possible obs: 99.9 % / Redundancy: 4.8 % / Biso Wilson estimate: 56.41 Å2 / Rsym value: 0.091 / Net I/σ(I): 15.1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
2.729-2.884.80.4421.8740515350.44299.9
2.88-3.054.80.2772.8699514560.277100
3.05-3.264.80.1924.1647113370.192100
3.26-3.524.80.1286.1620712830.128100
3.52-3.864.80.0819.6565511770.08199.9
3.86-4.324.80.06212.5513210650.06299.9
4.32-4.984.80.04218.145829580.04299.9
4.98-6.14.80.0515.338208030.0599.9
6.1-8.634.60.04517.230006490.045100
8.63-100.0524.20.02229.115843760.02297.6

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Processing

Software
NameVersionClassificationNB
SCALA3.3.16data scaling
BUSTER-TNTBUSTER 2.11.2refinement
PDB_EXTRACT3.1data extraction
d*TREKdata reduction
autoBUSTERphasing
BUSTER2.11.2refinement
RefinementMethod to determine structure: RIGID BODY REFINEMENT / Resolution: 2.73→51.91 Å / Cor.coef. Fo:Fc: 0.9273 / Cor.coef. Fo:Fc free: 0.853 / Occupancy max: 1 / Occupancy min: 1 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.368
RfactorNum. reflection% reflectionSelection details
Rfree0.2435 559 5.27 %RANDOM
Rwork0.1548 ---
obs0.1592 10610 99.79 %-
Displacement parametersBiso max: 148.58 Å2 / Biso mean: 40.8975 Å2 / Biso min: 8.66 Å2
Baniso -1Baniso -2Baniso -3
1-7.9953 Å20 Å20 Å2
2--8.0961 Å20 Å2
3----16.0914 Å2
Refine analyzeLuzzati coordinate error obs: 0.255 Å
Refinement stepCycle: LAST / Resolution: 2.73→51.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3103 0 30 119 3252
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1080SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes75HARMONIC2
X-RAY DIFFRACTIONt_gen_planes469HARMONIC5
X-RAY DIFFRACTIONt_it3220HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion413SEMIHARMONIC5
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_contact3663SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3220HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg4387HARMONIC21.2
X-RAY DIFFRACTIONt_omega_torsion3.1
X-RAY DIFFRACTIONt_other_torsion20.03
LS refinement shellResolution: 2.73→3.05 Å / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.3042 150 5.03 %
Rwork0.1713 2835 -
all0.1775 2985 -
obs--99.79 %

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