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- PDB-5he4: BACE-1 in complex with (4aR,7aS)-7a-(2,6-difluorophenyl)-6-(5-flu... -

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Basic information

Entry
Database: PDB / ID: 5he4
TitleBACE-1 in complex with (4aR,7aS)-7a-(2,6-difluorophenyl)-6-(5-fluoro-4-methoxy-6-methylpyrimidin-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 / amyloid-beta metabolic process / cellular response to manganese ion / 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 / amyloid-beta metabolic process / cellular response to manganese ion / 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 / multivesicular body / hippocampal mossy fiber to CA3 synapse / 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 / early endosome / lysosome / 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-60T / L(+)-TARTARIC ACID / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.53 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
Revision 1.2Nov 13, 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 / citation / database_2 / pdbx_entry_details / pdbx_modification_feature / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)93,4915
Polymers92,5002
Non-polymers9913
Water17,493971
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,6702
Polymers46,2501
Non-polymers4201
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,8203
Polymers46,2501
Non-polymers5702
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)86.390, 89.370, 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-60T / (2E,4aR,7aS)-7a-(2,6-difluorophenyl)-6-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-2-imino-3-methyloctahydro-4H-pyrrolo[3,4-d]pyrimidin-4-one


Mass: 420.388 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H19F3N6O2
#3: Chemical ChemComp-TLA / L(+)-TARTARIC ACID


Mass: 150.087 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H6O6
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 971 / 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: 2.94 Å3/Da / Density % sol: 58.15 %
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: ADSC QUANTUM 210 / Detector: CCD / Date: Jun 13, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.53→20 Å / Num. obs: 151652 / % possible obs: 98.7 % / Redundancy: 4.7 % / Rmerge(I) obs: 0.064 / Χ2: 1 / Net I/av σ(I): 19.943 / Net I/σ(I): 9.5 / Num. measured all: 710929
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allΧ2Diffraction-ID% possible all
1.53-1.564.50.5262.874121197.2
1.56-1.584.50.4723.173720.99797.2
1.58-1.624.50.4073.574581.00197.8
1.62-1.654.50.3683.774081.00597.7
1.65-1.684.50.3074.274951.00398.2
1.68-1.724.50.2734.674881.00298.1
1.72-1.774.50.2315.374521.00197.9
1.77-1.814.50.196674641.00198.3
1.81-1.874.50.1666.57535198.4
1.87-1.934.50.1427.47533198.6
1.93-24.50.1089.87542198.9
2-2.084.60.09311.27598198.8
2.08-2.174.60.08212.47585199.2
2.17-2.284.70.07513.47645199.5
2.28-2.434.80.06914.676810.99999.9
2.43-2.615.10.0621677221100
2.61-2.885.20.05418.777171100
2.88-3.295.30.04622.87773199.9
3.29-4.145.20.04126.17783199.3
4.14-204.80.03826.77989198.5

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
PDB_EXTRACT3.1data extraction
DENZOdata reduction
BUSTER2.11.6refinement
AMoREphasing
RefinementResolution: 1.53→19.9 Å / Cor.coef. Fo:Fc: 0.9585 / Cor.coef. Fo:Fc free: 0.9516 / Occupancy max: 1 / Occupancy min: 0.5 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2217 7559 5.01 %RANDOM
Rwork0.203 ---
obs0.204 150845 98.48 %-
Displacement parametersBiso max: 111.58 Å2 / Biso mean: 20.0398 Å2 / Biso min: 7.91 Å2
Baniso -1Baniso -2Baniso -3
1-2.6513 Å20 Å20 Å2
2---3.7201 Å20 Å2
3---1.0688 Å2
Refine analyzeLuzzati coordinate error obs: 0.2 Å
Refinement stepCycle: LAST / Resolution: 1.53→19.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6047 0 70 971 7088
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2092SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes143HARMONIC2
X-RAY DIFFRACTIONt_gen_planes965HARMONIC5
X-RAY DIFFRACTIONt_it6289HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion800SEMIHARMONIC5
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_contact8178SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d6289HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg8570HARMONIC21.04
X-RAY DIFFRACTIONt_omega_torsion4.58
X-RAY DIFFRACTIONt_other_torsion14.25
LS refinement shellResolution: 1.53→1.57 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2471 583 5.34 %
Rwork0.2201 10341 -
all0.2215 10924 -
obs--97.08 %

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