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- PDB-7myu: BACE-1 in complex with compound #22 -

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Basic information

Entry
Database: PDB / ID: 7myu
TitleBACE-1 in complex with compound #22
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / protease / 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 / cellular response to manganese ion / amyloid-beta metabolic process / 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 / cellular response to manganese ion / amyloid-beta metabolic process / prepulse inhibition / detection of mechanical stimulus involved in sensory perception of pain / cellular response to copper ion / presynaptic modulation of chemical synaptic transmission / hippocampal mossy fiber to CA3 synapse / multivesicular body / response to lead ion / trans-Golgi network / recycling endosome / protein processing / cellular response to amyloid-beta / positive regulation of neuron apoptotic process / synaptic vesicle / late endosome / 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. / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily
Similarity search - Domain/homology
Chem-ZR7 / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.94 Å
AuthorsHendle, J. / Timm, D.E. / Stout, S.L.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Discovery and Early Clinical Development of LY3202626, a Low-Dose, CNS-Penetrant BACE Inhibitor.
Authors: McKinzie, D.L. / Winneroski, L.L. / Green, S.J. / Hembre, E.J. / Erickson, J.A. / Willis, B.A. / Monk, S.A. / Aluise, C.D. / Baker, T.K. / Lopez, J.E. / Hendle, J. / Beck, J.P. / Brier, R.A. ...Authors: McKinzie, D.L. / Winneroski, L.L. / Green, S.J. / Hembre, E.J. / Erickson, J.A. / Willis, B.A. / Monk, S.A. / Aluise, C.D. / Baker, T.K. / Lopez, J.E. / Hendle, J. / Beck, J.P. / Brier, R.A. / Boggs, L.N. / Borders, A.R. / Cocke, P.J. / Garcia-Losada, P. / Lowe, S.L. / Mathes, B.M. / May, P.C. / Porter, W.J. / Stout, S.L. / Timm, D.E. / Watson, B.M. / Yang, Z. / Mergott, D.J.
History
DepositionMay 21, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 21, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 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

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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)99,0335
Polymers97,9402
Non-polymers1,0933
Water13,151730
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,4692
Polymers48,9701
Non-polymers4991
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,5653
Polymers48,9701
Non-polymers5952
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)86.516, 90.540, 131.082
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-ZR7 / N-{3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4a,5,6,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a(4H)-yl]-4-fluorophenyl}-5-methoxypyrazine-2-carboxamide


Mass: 498.508 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H20F2N8O2S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


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


Mass: 18.015 Da / Num. of mol.: 730 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 53.07 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
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: 0.97931 Å
DetectorType: RAYONIX MX225HE / Detector: CCD / Date: Mar 14, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97931 Å / Relative weight: 1
ReflectionResolution: 1.94→34 Å / Num. obs: 76824 / % possible obs: 99.7 % / Redundancy: 7.2 % / Rmerge(I) obs: 0.155 / Net I/σ(I): 7.8
Reflection shellResolution: 1.94→2.04 Å / Redundancy: 7.1 % / Rmerge(I) obs: 0.708 / Mean I/σ(I) obs: 2.5 / Num. unique obs: 11029 / % possible all: 99.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0103refinement
PDB_EXTRACT3.27data extraction
MOSFLMdata reduction
SCALAdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6UVP

6uvp


Resolution: 1.94→30 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.946 / SU B: 3.817 / SU ML: 0.104 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.138 / ESU R Free: 0.134 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2264 518 0.7 %RANDOM
Rwork0.1866 ---
obs0.1869 76070 99.66 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 111.79 Å2 / Biso mean: 24.129 Å2 / Biso min: 8.58 Å2
Baniso -1Baniso -2Baniso -3
1--0.19 Å20 Å20 Å2
2--0.94 Å2-0 Å2
3----0.75 Å2
Refinement stepCycle: final / Resolution: 1.94→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6069 0 75 730 6874
Biso mean--22.05 33.29 -
Num. residues----779
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0126448
X-RAY DIFFRACTIONr_angle_refined_deg1.1791.6528821
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.215824
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.40723.846286
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.697151010
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.6351536
X-RAY DIFFRACTIONr_chiral_restr0.0950.2837
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.025132
LS refinement shellResolution: 1.94→1.99 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.337 35 -
Rwork0.294 5553 -
all-5588 -
obs--99.34 %

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