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- PDB-2zjn: Crystal structure of the human BACE1 catalytic domain in complex ... -

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Basic information

Entry
Database: PDB / ID: 2zjn
TitleCrystal structure of the human BACE1 catalytic domain in complex with N-[1-(5-chloro-2-isopropoxy-3-methoxy-benzyl)-piperidin-4-yl]-2-(2-methyl-4-sulfamoyl-phenoxy)-acetamide
ComponentsBeta-secretase 1
KeywordsHYDROLASE / BACE1 / small-molecule inhibitor / fragment-based discovery / Alternative splicing / Aspartyl protease / Glycoprotein / Membrane / Protease / Transmembrane / Zymogen
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 / detection of mechanical stimulus involved in sensory perception of pain / amyloid-beta metabolic process / cellular response to manganese ion ...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 / detection of mechanical stimulus involved in sensory perception of pain / amyloid-beta metabolic process / cellular response to manganese ion / prepulse inhibition / 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 / positive regulation of neuron apoptotic process / cellular response to amyloid-beta / late endosome / synaptic vesicle / 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. / 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-F1N / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsRandal, M. / Lam, M.B. / Fahr, B.T. / Romanowski, M.J.
CitationJournal: To be Published
Title: Fragment-based discovery of novel BACE1 inhibitors using Tethering technology
Authors: Yang, W. / Fucini, R.V. / Fahr, B.T. / Randal, M. / Lind, K.E. / Lam, M.B. / Lu, W. / Lu, Y. / Cary, D.R. / Romanowski, M.J.
History
DepositionMar 7, 2008Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 20, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 1, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,7792
Polymers45,2391
Non-polymers5401
Water93752
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)103.989, 103.989, 167.081
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122

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Components

#1: Protein Beta-secretase 1 / Beta-site APP cleaving enzyme 1 / Beta-site amyloid precursor protein cleaving enzyme 1 / Membrane- ...Beta-site APP cleaving enzyme 1 / Beta-site amyloid precursor protein cleaving enzyme 1 / Membrane-associated aspartic protease 2 / Memapsin-2 / Aspartyl protease 2 / Asp 2 / ASP2


Mass: 45238.891 Da / Num. of mol.: 1 / Fragment: BACE1 catalytic domain, UNP residues 43-446
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1 / Plasmid: PET11A / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) Star / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-F1N / N-{1-[5-chloro-3-methoxy-2-(1-methylethoxy)benzyl]piperidin-4-yl}-2-(2-methyl-4-sulfamoylphenoxy)acetamide / N-[1-(5-chloro-2-isopropoxy-3-methoxy-benzyl)-piperidin-4-yl]-2-(2-methyl-4-sulfamoyl-phenoxy)-acetamide


Mass: 540.072 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H34ClN3O6S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 52 / 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: 2.88 Å3/Da / Density % sol: 57.33 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 6mg/ml BACE1, 0.1M HEPES pH 7.5, 1.5M Li2SO4, VAPOR DIFFUSION, SITTING DROP, temperature 295K

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Data collection

DiffractionMean temperature: 180 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Jan 14, 2005
RadiationMonochromator: YALE MIRRORS / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.7→20 Å / Num. all: 15302 / Num. obs: 15191 / % possible obs: 99.7 % / Rmerge(I) obs: 0.097
Reflection shellResolution: 2.7→2.8 Å / Rmerge(I) obs: 0.328

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
CrystalCleardata collection
d*TREKdata reduction
d*TREKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2P8H

2p8h


Resolution: 2.7→20 Å / Cor.coef. Fo:Fc: 0.913 / Cor.coef. Fo:Fc free: 0.88 / SU B: 12.39 / SU ML: 0.254 / Cross valid method: THROUGHOUT / ESU R: 0.663 / ESU R Free: 0.325 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.25977 748 4.9 %RANDOM
Rwork0.22212 ---
obs0.22395 14385 99.28 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 38.158 Å2
Baniso -1Baniso -2Baniso -3
1--0.75 Å2-0.37 Å20 Å2
2---0.75 Å20 Å2
3---1.12 Å2
Refinement stepCycle: LAST / Resolution: 2.7→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2878 0 36 52 2966
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0222992
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg0.8811.964071
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.8075363
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.8923.582134
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.34515461
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.5431517
X-RAY DIFFRACTIONr_chiral_restr0.0550.2441
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.022293
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.1630.21238
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3020.22001
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1040.2127
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1360.241
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1040.25
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.2412.51859
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.15252935
X-RAY DIFFRACTIONr_scbond_it0.9382.51317
X-RAY DIFFRACTIONr_scangle_it1.54951136
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.7→2.793 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.35 60 -
Rwork0.299 1347 -
obs--98.6 %

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