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- PDB-6uvp: BACE-1 in complex with compound #3 -

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Basic information

Entry
Database: PDB / ID: 6uvp
TitleBACE-1 in complex with compound #3
ComponentsBeta-secretase 1
KeywordsHYDROLASE/INHIBITOR / protease / inhibitor / complex / 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-beta formation / amyloid precursor protein catabolic process / membrane protein ectodomain proteolysis / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / prepulse inhibition ...memapsin 2 / Golgi-associated vesicle lumen / beta-aspartyl-peptidase activity / signaling receptor ligand precursor processing / amyloid-beta formation / amyloid precursor protein catabolic process / membrane protein ectodomain proteolysis / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / prepulse inhibition / cellular response to manganese ion / multivesicular body / presynaptic modulation of chemical synaptic transmission / protein serine/threonine kinase binding / cellular response to copper ion / hippocampal mossy fiber to CA3 synapse / trans-Golgi network / recycling endosome / protein processing / response to lead ion / cellular response to amyloid-beta / synaptic vesicle / late endosome / peptidase activity / positive regulation of neuron apoptotic process / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / aspartic-type endopeptidase activity / early endosome / lysosome / endosome membrane / endosome / membrane raft / endoplasmic reticulum lumen / Amyloid fiber formation / 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-QJJ / Chem-QJM / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.56 Å
AuthorsHendle, J. / Timm, D.E.
CitationJournal: Bioorg.Med.Chem. / Year: 2020
Title: Preparation and biological evaluation of BACE1 inhibitors: Leveraging trans-cyclopropyl moieties as ligand efficient conformational constraints.
Authors: Winneroski, L.L. / Erickson, J.A. / Green, S.J. / Lopez, J.E. / Stout, S.L. / Porter, W.J. / Timm, D.E. / Audia, J.E. / Barberis, M. / Beck, J.P. / Boggs, L.N. / Borders, A.R. / Boyer, R.D. ...Authors: Winneroski, L.L. / Erickson, J.A. / Green, S.J. / Lopez, J.E. / Stout, S.L. / Porter, W.J. / Timm, D.E. / Audia, J.E. / Barberis, M. / Beck, J.P. / Boggs, L.N. / Borders, A.R. / Boyer, R.D. / Brier, R.A. / Hembre, E.J. / Hendle, J. / Garcia-Losada, P. / Minguez, J.M. / Mathes, B.M. / May, P.C. / Monk, S.A. / Rankovic, Z. / Shi, Y. / Watson, B.M. / Yang, Z. / Mergott, D.J.
History
DepositionNov 4, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 11, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 1, 2020Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.year
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)100,61515
Polymers97,9402
Non-polymers2,67513
Water19,8891104
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,9236
Polymers48,9701
Non-polymers9535
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,6929
Polymers48,9701
Non-polymers1,7228
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)86.548, 90.294, 131.583
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#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: 48970.117 Da / Num. of mol.: 2
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

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Non-polymers , 5 types, 1117 molecules

#2: Chemical
ChemComp-QJJ / N-{(1S,2S)-2-[(4aS,7aR)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a(7H)-yl]cyclopropyl}-5-fluoropyridine-2-carboxamide


Mass: 336.384 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C15H17FN4O2S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-QJM / N-{(1R,2R)-2-[(4aS,7aR)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a(7H)-yl]cyclopropyl}-5-fluoropyridine-2-carboxamide


Mass: 336.384 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H17FN4O2S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1104 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
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: 2.62 Å3/Da / Density % sol: 53.14 %
Crystal growTemperature: 277 K / Method: vapor diffusion
Details: 100mM Sodium Cacodylate pH 7.4, 12% PEG 8K, 200mM Ammonium Sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.97929 Å
DetectorType: RAYONIX MX225HE / Detector: CCD / Date: Feb 18, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97929 Å / Relative weight: 1
ReflectionResolution: 1.56→99.99 Å / Num. obs: 146798 / % possible obs: 99.9 % / Redundancy: 7.4 % / Biso Wilson estimate: 13.5 Å2 / Rmerge(I) obs: 0.1 / Net I/σ(I): 10.9
Reflection shellResolution: 1.56→1.64 Å / Redundancy: 7.4 % / Rmerge(I) obs: 0.661 / Num. unique obs: 21253 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0103refinement
PDB_EXTRACT3.25data extraction
MOSFLMdata reduction
SCALAdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 6BFE

6bfe


Resolution: 1.56→30 Å / Cor.coef. Fo:Fc: 0.978 / Cor.coef. Fo:Fc free: 0.961 / SU B: 2.711 / SU ML: 0.043 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.066 / ESU R Free: 0.064
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1819 1021 0.7 %RANDOM
Rwork0.1378 ---
obs0.1381 145698 99.95 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 82.44 Å2 / Biso mean: 18.445 Å2 / Biso min: 5.53 Å2
Baniso -1Baniso -2Baniso -3
1--0.5 Å2-0 Å20 Å2
2--1.06 Å2-0 Å2
3----0.55 Å2
Refinement stepCycle: final / Resolution: 1.56→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6074 0 187 1106 7367
Biso mean--25.85 32.94 -
Num. residues----776
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0126539
X-RAY DIFFRACTIONr_angle_refined_deg1.2461.6778938
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9395809
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.47823.889288
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.04151017
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.8461536
X-RAY DIFFRACTIONr_chiral_restr0.090.2857
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.024938
X-RAY DIFFRACTIONr_rigid_bond_restr2.25936539
X-RAY DIFFRACTIONr_sphericity_free20.7365669
X-RAY DIFFRACTIONr_sphericity_bonded12.05256796
LS refinement shellResolution: 1.56→1.6 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.225 67 -
Rwork0.197 10662 -
all-10729 -
obs--99.89 %

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