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- PDB-5hdz: BACE-1 in complex with (7aR)-7a-(5-cyanothiophen-2-yl)-6-(5-fluor... -

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Basic information

Entry
Database: PDB / ID: 5hdz
TitleBACE-1 in complex with (7aR)-7a-(5-cyanothiophen-2-yl)-6-(5-fluoro-4-methyl-6-(methylthio)pyrimidin-2-yl)-3-methyl-4-oxooctahydro-2H-pyrrolo[3,4-d]pyrimidin-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 / 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-954 / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.49 Å
AuthorsOrth, P.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Structure-Based Design of an Iminoheterocyclic beta-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central A beta in Nonhuman Primates.
Authors: Mandal, M. / Wu, Y. / Misiaszek, J. / Li, G. / Buevich, A. / Caldwell, J.P. / Liu, X. / Mazzola, R.D. / Orth, P. / Strickland, C. / Voigt, J. / Wang, H. / Zhu, Z. / Chen, X. / Grzelak, M. / ...Authors: Mandal, M. / Wu, Y. / Misiaszek, J. / Li, G. / Buevich, A. / Caldwell, J.P. / Liu, X. / Mazzola, R.D. / Orth, P. / Strickland, C. / Voigt, J. / Wang, H. / Zhu, Z. / Chen, X. / Grzelak, M. / Hyde, L.A. / Kuvelkar, R. / Leach, P.T. / Terracina, G. / Zhang, L. / Zhang, Q. / Michener, M.S. / Smith, B. / Cox, K. / Grotz, D. / Favreau, L. / Mitra, K. / Kazakevich, I. / McKittrick, B.A. / Greenlee, W. / Kennedy, M.E. / Parker, E.M. / Cumming, J.N. / Stamford, A.W.
History
DepositionJan 5, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 16, 2016Provider: repository / Type: Initial release
Revision 1.1Apr 27, 2016Group: 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)93,3634
Polymers92,5002
Non-polymers8632
Water16,141896
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,6812
Polymers46,2501
Non-polymers4321
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,6812
Polymers46,2501
Non-polymers4321
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)86.303, 89.914, 131.554
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: 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-954 / 5-{(2E,4aR,7aR)-6-[5-fluoro-4-methyl-6-(methylsulfanyl)pyrimidin-2-yl]-2-imino-3-methyl-4-oxooctahydro-7aH-pyrrolo[3,4-d]pyrimidin-7a-yl}thiophene-2-carbonitrile


Mass: 431.510 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H18FN7OS2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 896 / 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: 2.97 Å3/Da / Density % sol: 58.54 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 15% PEG 3350, 200mM Na/K tartrate, 100mM Hepes

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 25, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.49→131.554 Å / Num. obs: 164629 / % possible obs: 98.7 % / Redundancy: 6.6 % / Net I/σ(I): 11.6 / Num. measured all: 1089154

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Processing

Software
NameVersionClassification
PDB_EXTRACT3.1data extraction
XDSdata reduction
SCALAdata scaling
BUSTER2.11.6refinement
AMoREphasing
RefinementResolution: 1.49→62.26 Å / Cor.coef. Fo:Fc: 0.9488 / Cor.coef. Fo:Fc free: 0.9492 / Occupancy max: 1 / Occupancy min: 0.5 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2068 6485 4.01 %RANDOM
Rwork0.1942 ---
obs0.1947 161753 96.86 %-
Displacement parametersBiso max: 113.78 Å2 / Biso mean: 19.9315 Å2 / Biso min: 6.83 Å2
Baniso -1Baniso -2Baniso -3
1-4.0699 Å20 Å20 Å2
2---4.9569 Å20 Å2
3---0.8871 Å2
Refine analyzeLuzzati coordinate error obs: 0.198 Å
Refinement stepCycle: LAST / Resolution: 1.49→62.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6023 0 58 896 6977
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2071SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes141HARMONIC2
X-RAY DIFFRACTIONt_gen_planes952HARMONIC5
X-RAY DIFFRACTIONt_it6242HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion795SEMIHARMONIC5
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_contact8005SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d6242HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg8503HARMONIC21.05
X-RAY DIFFRACTIONt_omega_torsion4.62
X-RAY DIFFRACTIONt_other_torsion13.88
LS refinement shellResolution: 1.49→1.53 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2095 466 4 %
Rwork0.1978 11186 -
all0.1983 11652 -
obs--95.37 %

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