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- PDB-2irz: Crystal structure of human Beta-secretase complexed with inhibitor -

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Basic information

Entry
Database: PDB / ID: 2irz
TitleCrystal structure of human Beta-secretase complexed with inhibitor
ComponentsBeta-secretase 1
KeywordsHYDROLASE / Aspartyl Protease
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 / presynaptic modulation of chemical synaptic transmission / multivesicular body / 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-I02 / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsMunshi, S.
CitationJournal: J.Med.Chem. / Year: 2006
Title: Discovery of oxadiazoyl tertiary carbinamine inhibitors of beta-secretase (BACE-1).
Authors: Rajapakse, H.A. / Nantermet, P.G. / Selnick, H.G. / Munshi, S. / McGaughey, G.B. / Lindsley, S.R. / Young, M.B. / Lai, M.T. / Espeseth, A.S. / Shi, X.P. / Colussi, D. / Pietrak, B. / ...Authors: Rajapakse, H.A. / Nantermet, P.G. / Selnick, H.G. / Munshi, S. / McGaughey, G.B. / Lindsley, S.R. / Young, M.B. / Lai, M.T. / Espeseth, A.S. / Shi, X.P. / Colussi, D. / Pietrak, B. / Crouthamel, M.C. / Tugusheva, K. / Huang, Q. / Xu, M. / Simon, A.J. / Kuo, L. / Hazuda, D.J. / Graham, S. / Vacca, J.P.
History
DepositionOct 16, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 14, 2006Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2007Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 20, 2021Group: Database references / Derived calculations / Category: database_2 / 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 1.4Aug 30, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.5Oct 16, 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)45,6742
Polymers45,1231
Non-polymers5521
Water5,296294
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)104.53, 127.78, 76.47
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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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: 45122.750 Da / Num. of mol.: 1 / Fragment: protease domain / Mutation: K75A, E77A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE / Plasmid: PET11A / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-I02 / 3-{5-[(1R)-1-AMINO-1-METHYL-2-PHENYLETHYL]-1,3,4-OXADIAZOL-2-YL}-N-[(1R)-1-(4-FLUOROPHENYL)ETHYL]-5-[METHYL(METHYLSULFONYL)AMINO]BENZAMIDE


Mass: 551.632 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H30FN5O4S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 294 / 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: 2.83 Å3/Da / Density % sol: 56.49 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 1.5M Lithium sulfate, 0.1M HEPES buffer, pH 7.5, VAPOR DIFFUSION, SITTING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Jan 24, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.8→50 Å / Num. all: 45288 / Num. obs: 45288 / % possible obs: 94.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3 % / Rmerge(I) obs: 0.087 / Net I/σ(I): 23.5
Reflection shellResolution: 1.8→1.86 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.585 / Mean I/σ(I) obs: 2 / Num. unique all: 4715 / % possible all: 96.8

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Processing

Software
NameVersionClassification
CNXVERSION 2000.1refinement
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
CNX2000.1phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1TQF

1tqf


Resolution: 1.8→6 Å / σ(F): 0 / σ(I): 0
RfactorNum. reflection% reflection
Rfree0.24 4195 -
Rwork0.219 --
all0.219 41607 -
obs0.219 41607 89.8 %
Refinement stepCycle: LAST / Resolution: 1.8→6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2979 0 39 294 3312

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