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- PDB-1fkn: Structure of Beta-Secretase Complexed with Inhibitor -

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Basic information

Entry
Database: PDB / ID: 1fkn
TitleStructure of Beta-Secretase Complexed with Inhibitor
Components
  • MEMAPSIN 2Beta-secretase 1
  • inhibitorEnzyme inhibitor
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Alzheimer's disease / beta-secretase / memapsin 2 / BASE / aspartic 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 / prepulse inhibition / amyloid-beta metabolic process ...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 / prepulse inhibition / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / cellular response to copper ion / hippocampal mossy fiber to CA3 synapse / presynaptic modulation of chemical synaptic transmission / multivesicular body / response to lead ion / trans-Golgi network / protein processing / recycling endosome / cellular response to amyloid-beta / positive regulation of neuron apoptotic process / synaptic vesicle / late endosome / amyloid-beta binding / peptidase activity / endopeptidase activity / amyloid fibril formation / lysosome / aspartic-type endopeptidase activity / early endosome / endosome membrane / endosome / membrane raft / Amyloid fiber formation / axon / endoplasmic reticulum lumen / dendrite / neuronal cell body / 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
BETA-SECRETASE INHIBITOR OM99-2 / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Resolution: 1.9 Å
AuthorsHong, L. / Koelsch, G. / Lin, X. / Wu, S. / Terzyan, S. / Ghosh, A. / Zhang, X.C. / Tang, J.
CitationJournal: Science / Year: 2000
Title: Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor.
Authors: Hong, L. / Koelsch, G. / Lin, X. / Wu, S. / Terzyan, S. / Ghosh, A.K. / Zhang, X.C. / Tang, J.
History
DepositionAug 9, 2000Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Oct 9, 2000Provider: repository / Type: Initial release
Revision 1.1Jan 8, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
Revision 1.3Dec 12, 2012Group: Other
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / database_2 / pdbx_validate_main_chain_plane / pdbx_validate_peptide_omega / pdbx_validate_rmsd_angle / struct_conn
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_validate_peptide_omega.auth_comp_id_1 / _pdbx_validate_peptide_omega.auth_comp_id_2 / _pdbx_validate_peptide_omega.auth_seq_id_1 / _pdbx_validate_peptide_omega.auth_seq_id_2 / _pdbx_validate_peptide_omega.omega / _struct_conn.pdbx_leaving_atom_flag

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: MEMAPSIN 2
B: MEMAPSIN 2
C: inhibitor
D: inhibitor


Theoretical massNumber of molelcules
Total (without water)89,0404
Polymers89,0404
Non-polymers00
Water9,530529
1
A: MEMAPSIN 2
C: inhibitor


Theoretical massNumber of molelcules
Total (without water)44,5202
Polymers44,5202
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: MEMAPSIN 2
D: inhibitor


Theoretical massNumber of molelcules
Total (without water)44,5202
Polymers44,5202
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)53.652, 85.853, 109.237
Angle α, β, γ (deg.)90.00, 101.36, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein MEMAPSIN 2 / Beta-secretase 1 / BETA-SECRETASE


Mass: 43627.191 Da / Num. of mol.: 2 / Fragment: PROTEASE DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: PET11A / Production host: Escherichia coli (E. coli) / References: UniProt: P56817, memapsin 2
#2: Protein/peptide inhibitor / Enzyme inhibitor


Type: Peptide-like / Class: Inhibitor / Mass: 892.992 Da / Num. of mol.: 2 / Source method: obtained synthetically / References: BETA-SECRETASE INHIBITOR OM99-2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 529 / Source method: isolated from a natural source / Formula: H2O

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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: 2.77 Å3/Da / Density % sol: 55.59 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.4
Details: 22.5% PEG 8000, 0.1M Na-cacodylate, 0.2M ammonium sulfate, pH 7.4, VAPOR DIFFUSION, HANGING DROP, temperature 293K
Crystal
*PLUS
Density % sol: 56 %
Crystal grow
*PLUS
Temperature: 20 ℃
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-ID
10.2 Mammonium sulfate1reservoir
222.5 %PEG80001reservoir
30.1 Msodium cacodylate1reservoir

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Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.5418
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Feb 14, 2000
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.9→25 Å / Num. all: 144164 / Num. obs: 69056 / % possible obs: 90 % / Observed criterion σ(F): 3 / Observed criterion σ(I): 3 / Redundancy: 2 % / Biso Wilson estimate: 25 Å2 / Rmerge(I) obs: 0.061 / Net I/σ(I): 13.7
Reflection shellResolution: 1.9→2 Å / Rmerge(I) obs: 0.25 / % possible all: 68.5
Reflection
*PLUS
Lowest resolution: 25 Å / % possible obs: 90 % / Num. measured all: 144164
Reflection shell
*PLUS
Lowest resolution: 2 Å / % possible obs: 68.5 % / Mean I/σ(I) obs: 3

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Processing

Software
NameVersionClassification
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
CNS1refinement
RefinementResolution: 1.9→24.9 Å / Rfactor Rfree error: 0.003 / Data cutoff high absF: 340489.22 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.224 6748 10.1 %RANDOM
Rwork0.18 ---
obs0.18 69056 90 %-
all-144164 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 68.74 Å2 / ksol: 0.434 e/Å3
Displacement parametersBiso mean: 29.2 Å2
Baniso -1Baniso -2Baniso -3
1-12.96 Å20 Å27.73 Å2
2---8.93 Å20 Å2
3----4.03 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.24 Å0.19 Å
Luzzati d res low-5 Å
Luzzati sigma a0.19 Å0.17 Å
Refinement stepCycle: LAST / Resolution: 1.9→24.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6254 0 0 529 6783
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.014
X-RAY DIFFRACTIONc_angle_deg1.8
X-RAY DIFFRACTIONc_dihedral_angle_d26.1
X-RAY DIFFRACTIONc_improper_angle_d1.12
LS refinement shellResolution: 1.9→2.02 Å / Rfactor Rfree error: 0.01 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.274 771 10.1 %
Rwork0.248 6833 -
obs--59.8 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2OM99.PARAMOM99.TOP
X-RAY DIFFRACTION3WATER_REP.PARAM
Software
*PLUS
Name: CNS / Version: 1 / Classification: refinement
Refinement
*PLUS
σ(F): 0 / % reflection Rfree: 10.1 % / Rfactor obs: 0.18 / Rfactor Rwork: 0.18
Solvent computation
*PLUS
Displacement parameters
*PLUS
Biso mean: 29.2 Å2
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_angle_deg1.8
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg26.1
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg1.12
LS refinement shell
*PLUS
Rfactor Rfree: 0.274 / % reflection Rfree: 10.1 % / Rfactor Rwork: 0.248

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