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- PDB-5hdu: BACE-1 incomplex with (7aR)-7a-(4-(3-cyanophenyl)thiophen-2-yl)-6... -

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Basic information

Entry
Database: PDB / ID: 5hdu
TitleBACE-1 incomplex with (7aR)-7a-(4-(3-cyanophenyl)thiophen-2-yl)-6-(5-fluoro-4-methoxypyrimidin-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 / 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-60W / L(+)-TARTARIC ACID / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.58 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

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Assembly

Deposited unit
A: Beta-secretase 1
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)93,7556
Polymers92,5002
Non-polymers1,2554
Water16,177898
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,8783
Polymers46,2501
Non-polymers6282
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,8783
Polymers46,2501
Non-polymers6282
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)86.410, 89.450, 131.240
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-TLA / L(+)-TARTARIC ACID


Mass: 150.087 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H6O6
#3: Chemical ChemComp-60W / 3-{5-[(2E,4aR,7aR)-6-(5-fluoro-4-methoxypyrimidin-2-yl)-2-imino-3-methyl-4-oxooctahydro-7aH-pyrrolo[3,4-d]pyrimidin-7a-yl]thiophen-3-yl}benzonitrile


Mass: 477.514 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H20FN7O2S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 898 / 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: 2.94 Å3/Da / Density % sol: 58.2 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 15% PEG 3350, 200mM Na/K tartrate, 100mM Hepes / PH range: 7

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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: Jul 21, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.58→20 Å / Num. obs: 139125 / % possible obs: 99.7 % / Redundancy: 4.9 % / Rmerge(I) obs: 0.064 / Χ2: 1 / Net I/av σ(I): 20.19 / Net I/σ(I): 9.4 / Num. measured all: 687097
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allΧ2Diffraction-ID% possible all
1.58-1.614.80.5222.969031199.7
1.61-1.644.80.4743.269040.99499.9
1.64-1.674.80.4143.568681.00199.8
1.67-1.74.80.3673.769011.00399.9
1.7-1.744.80.3244.269051.00299.9
1.74-1.784.80.266569091.00299.8
1.78-1.824.80.2235.469141.00199.9
1.82-1.874.90.196.26895199.9
1.87-1.934.90.1676.66937199.9
1.93-1.9950.1239.56917199.9
1.99-2.0650.10211.36933199.9
2.06-2.145.10.09611.76960199.9
2.14-2.245.10.08213.76940199.9
2.24-2.365.10.0813.36949199.8
2.36-2.515.10.06915.46974199.9
2.51-2.75.10.06117.47015199.9
2.7-2.975.10.05120.37015199.8
2.97-3.45.10.04324.27021199.7
3.4-4.2850.03825.570911.00199.3
4.28-204.70.03427.17174197.3

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
PDB_EXTRACT3.1data extraction
DENZOdata reduction
BUSTER2.11.6refinement
AMoREphasing
RefinementResolution: 1.58→19.91 Å / Cor.coef. Fo:Fc: 0.9576 / Cor.coef. Fo:Fc free: 0.95 / Occupancy max: 1 / Occupancy min: 0.5 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2138 6980 5.03 %RANDOM
Rwork0.1922 ---
obs0.1933 138790 99.58 %-
Displacement parametersBiso max: 115.59 Å2 / Biso mean: 22.5027 Å2 / Biso min: 8.74 Å2
Baniso -1Baniso -2Baniso -3
1-3.7071 Å20 Å20 Å2
2---5.4328 Å20 Å2
3---1.7257 Å2
Refine analyzeLuzzati coordinate error obs: 0.202 Å
Refinement stepCycle: LAST / Resolution: 1.58→19.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6052 0 88 898 7038
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2101SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes144HARMONIC2
X-RAY DIFFRACTIONt_gen_planes983HARMONIC5
X-RAY DIFFRACTIONt_it6311HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion802SEMIHARMONIC5
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_contact7939SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d6311HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg8599HARMONIC21.04
X-RAY DIFFRACTIONt_omega_torsion4.51
X-RAY DIFFRACTIONt_other_torsion14.38
LS refinement shellResolution: 1.58→1.62 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2467 551 5.39 %
Rwork0.212 9668 -
all0.2138 10219 -
obs--99.72 %

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