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- PDB-6uwv: BACE-1 in complex with compound #34 -

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Basic information

Entry
Database: PDB / ID: 6uwv
TitleBACE-1 in complex with compound #34
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 / endosome membrane / 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-QK7 / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.47 Å
AuthorsHendle, J. / Stout, S.L.
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 5, 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 1.3Nov 6, 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)99,39211
Polymers97,9402
Non-polymers1,4529
Water19,0601058
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,5564
Polymers48,9701
Non-polymers5863
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,8367
Polymers48,9701
Non-polymers8666
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)86.489, 89.694, 131.374
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: 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
#2: Chemical ChemComp-QK7 / (4aR,7aR)-7a-[(1R,2R)-2-(2-{[(1R,2R)-2-methylcyclopropyl]methoxy}propan-2-yl)cyclopropyl]-6-(pyrimidin-2-yl)-4,4a,5,6,7,7a-hexahydropyrrolo[3,4-d][1,3]thiazin-2-amine


Mass: 401.569 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H31N5OS / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1058 / Source method: isolated from a natural source / Formula: H2O
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: 2.6 Å3/Da / Density % sol: 52.72 %
Crystal growTemperature: 281 K / Method: vapor diffusion
Details: 100mM Sodium Cacodylate pH 7.4, 14% 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: 0.97931 Å
DetectorType: RAYONIX MX225HE / Detector: CCD / Date: Nov 5, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97931 Å / Relative weight: 1
ReflectionResolution: 1.47→99.99 Å / Num. obs: 171979 / % possible obs: 99.3 % / Redundancy: 5.5 % / Rmerge(I) obs: 0.083 / Net I/σ(I): 11
Reflection shellResolution: 1.47→1.55 Å / Redundancy: 5.3 % / Rmerge(I) obs: 0.454 / Mean I/σ(I) obs: 3.1 / Num. unique obs: 25011 / % possible all: 99.7

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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: 1.47→30 Å / Cor.coef. Fo:Fc: 0.979 / Cor.coef. Fo:Fc free: 0.973 / SU B: 2.031 / SU ML: 0.034 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.058 / ESU R Free: 0.051
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1595 8398 4.9 %RANDOM
Rwork0.137 ---
obs0.138 163566 99.09 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 113.5 Å2 / Biso mean: 15.531 Å2 / Biso min: 3.19 Å2
Baniso -1Baniso -2Baniso -3
1--0.47 Å2-0 Å20 Å2
2--0.72 Å2-0 Å2
3----0.25 Å2
Refinement stepCycle: final / Resolution: 1.47→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6116 0 97 1071 7284
Biso mean--17.4 26.83 -
Num. residues----780
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0126659
X-RAY DIFFRACTIONr_angle_refined_deg1.2781.6569126
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.115866
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.9223.876307
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.566151077
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.491540
X-RAY DIFFRACTIONr_chiral_restr0.090.2881
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.025072
X-RAY DIFFRACTIONr_rigid_bond_restr3.11136659
X-RAY DIFFRACTIONr_sphericity_free17.1875689
X-RAY DIFFRACTIONr_sphericity_bonded11.72556831
LS refinement shellResolution: 1.47→1.508 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.237 642 -
Rwork0.207 11976 -
all-12618 -
obs--99.58 %

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