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- PDB-5hu1: BACE1 in complex with (R)-N-(3-(3-amino-2,5-dimethyl-1,1-dioxido-... -

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Basic information

Entry
Database: PDB / ID: 5hu1
TitleBACE1 in complex with (R)-N-(3-(3-amino-2,5-dimethyl-1,1-dioxido-5,6-dihydro-2H-1,2,4-thiadiazin-5-yl)-4-fluorophenyl)-5-fluoropicolinamide
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 / beta-aspartyl-peptidase activity / signaling receptor ligand precursor processing / 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 / beta-aspartyl-peptidase activity / signaling receptor ligand precursor processing / 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 / cellular response to copper ion / protein serine/threonine kinase binding / multivesicular body / presynaptic modulation of chemical synaptic transmission / hippocampal mossy fiber to CA3 synapse / trans-Golgi network / response to lead ion / protein processing / recycling endosome / 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 / endosome membrane / membrane raft / Amyloid fiber formation / endoplasmic reticulum lumen / axon / neuronal cell body / dendrite / enzyme binding / cell surface / Golgi apparatus / 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-66F / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.5 Å
AuthorsOrth, P.
CitationJournal: J. Med. Chem. / Year: 2016
Title: Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)-A beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer's Disease.
Authors: Scott, J.D. / Li, S.W. / Brunskill, A.P. / Chen, X. / Cox, K. / Cumming, J.N. / Forman, M. / Gilbert, E.J. / Hodgson, R.A. / Hyde, L.A. / Jiang, Q. / Iserloh, U. / Kazakevich, I. / Kuvelkar, ...Authors: Scott, J.D. / Li, S.W. / Brunskill, A.P. / Chen, X. / Cox, K. / Cumming, J.N. / Forman, M. / Gilbert, E.J. / Hodgson, R.A. / Hyde, L.A. / Jiang, Q. / Iserloh, U. / Kazakevich, I. / Kuvelkar, R. / Mei, H. / Meredith, J. / Misiaszek, J. / Orth, P. / Rossiter, L.M. / Slater, M. / Stone, J. / Strickland, C.O. / Voigt, J.H. / Wang, G. / Wang, H. / Wu, Y. / Greenlee, W.J. / Parker, E.M. / Kennedy, M.E. / Stamford, A.W.
History
DepositionJan 27, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 9, 2016Provider: repository / Type: Initial release
Revision 1.1Nov 30, 2016Group: Database references
Revision 1.2Jan 4, 2017Group: Database references
Revision 1.3Nov 20, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)92,7784
Polymers91,9592
Non-polymers8192
Water16,123895
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,3892
Polymers45,9801
Non-polymers4091
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,3892
Polymers45,9801
Non-polymers4091
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)87.050, 90.200, 131.360
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: 45979.578 Da / Num. of mol.: 2 / Fragment: UNP residues 43-454
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-66F / N-{3-[(5R)-3-amino-2,5-dimethyl-1,1-dioxido-5,6-dihydro-2H-1,2,4-thiadiazin-5-yl]-4-fluorophenyl}-5-fluoropyridine-2-carboxamide


Mass: 409.410 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H17F2N5O3S / Comment: inhibitor*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 895 / 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: 2.99 Å3/Da / Density % sol: 58.89 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 15% PEG 3350, 200MM NA/K TARTRATE, 100MM HEPES PH7

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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: Mar 20, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.5→50 Å / Num. obs: 163466 / % possible obs: 99.7 % / Redundancy: 5 % / Rmerge(I) obs: 0.072 / Χ2: 1.071 / Net I/av σ(I): 19.187 / Net I/σ(I): 6.2 / Num. measured all: 820641
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
1.5-1.5350.86321100
1.53-1.555.10.7482.21100
1.55-1.5850.6752.51100
1.58-1.6250.5522.81100
1.62-1.654.90.493.1199.8
1.65-1.694.70.4033.6199.8
1.69-1.734.90.3494199.9
1.73-1.784.80.2754.8199.9
1.78-1.835.20.2295.7199.9
1.83-1.895.20.1886.9199.9
1.89-1.965.10.1597.7199.9
1.96-2.045.10.1189.6199.7
2.04-2.134.80.10110.6199.2
2.13-2.2450.08912.11100
2.24-2.385.20.07814.2199.9
2.38-2.565.30.06815.9199.9
2.56-2.825.10.05817.2199.6
2.82-3.234.90.04919.2198.7
3.23-4.075.20.03924199.4
4.07-504.90.03329.2198.7

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
DENZOdata reduction
SCALEPACKdata scaling
PDB_EXTRACT3.1data extraction
AMoREphasing
RefinementResolution: 1.5→45.33 Å / Cor.coef. Fo:Fc: 0.9599 / Cor.coef. Fo:Fc free: 0.9566 / Occupancy max: 1 / Occupancy min: 0.5 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2006 6573 4.02 %RANDOM
Rwork0.1847 ---
obs0.1853 163376 98.79 %-
Displacement parametersBiso max: 114.9 Å2 / Biso mean: 21.235 Å2 / Biso min: 8.56 Å2
Baniso -1Baniso -2Baniso -3
1-3.9898 Å20 Å20 Å2
2---6.0724 Å20 Å2
3---2.0826 Å2
Refine analyzeLuzzati coordinate error obs: 0.196 Å
Refinement stepCycle: LAST / Resolution: 1.5→45.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6042 0 56 895 6993
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2070SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes144HARMONIC2
X-RAY DIFFRACTIONt_gen_planes933HARMONIC5
X-RAY DIFFRACTIONt_it6270HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion801SEMIHARMONIC5
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_contact7888SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d6270HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg8546HARMONIC21.06
X-RAY DIFFRACTIONt_omega_torsion4.55
X-RAY DIFFRACTIONt_other_torsion14.49
LS refinement shellResolution: 1.5→1.54 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2439 447 4.23 %
Rwork0.2219 10110 -
all0.2228 10557 -
obs--87.47 %

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