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- PDB-1m4h: Crystal Structure of Beta-secretase complexed with Inhibitor OM00-3 -

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Basic information

Entry
Database: PDB / ID: 1m4h
TitleCrystal Structure of Beta-secretase complexed with Inhibitor OM00-3
Components
  • Inhibitor OM00-3
  • beta-Secretase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / MEMAPSIN2 / BASE / ASP2 / ALZHEIMER'S DISEASE / ASPARTIC PROTEASE / ACID 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 OM00-3 / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsHong, L. / Turner, R.T. / Koelsch, G. / Ghosh, A.K. / Tang, J.
CitationJournal: Biochemistry / Year: 2002
Title: Crystal Structure of Memapsin 2 (beta-Secretase) in Complex with Inhibitor OM00-3
Authors: Hong, L. / Turner, R.T. / Koelsch, G. / Shin, D. / Ghosh, A.K. / Tang, J.
History
DepositionJul 2, 2002Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 28, 2002Provider: repository / Type: Initial release
Revision 1.1Apr 28, 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 1.4Apr 5, 2017Group: Other
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations / Refinement description
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: beta-Secretase
B: beta-Secretase
C: Inhibitor OM00-3
D: Inhibitor OM00-3


Theoretical massNumber of molelcules
Total (without water)89,1264
Polymers89,1264
Non-polymers00
Water8,107450
1
A: beta-Secretase
C: Inhibitor OM00-3


Theoretical massNumber of molelcules
Total (without water)44,5632
Polymers44,5632
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1610 Å2
ΔGint-7 kcal/mol
Surface area16400 Å2
MethodPISA
2
B: beta-Secretase
D: Inhibitor OM00-3


Theoretical massNumber of molelcules
Total (without water)44,5632
Polymers44,5632
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1590 Å2
ΔGint-8 kcal/mol
Surface area16090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)86.450, 88.787, 130.954
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein beta-Secretase / / Memapsin-2


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) / Gene: BACE / Production host: Escherichia coli (E. coli)
References: UniProt: P56817, Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases
#2: Protein/peptide Inhibitor OM00-3


Type: Peptide-like / Class: Inhibitor / Mass: 936.057 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) / References: BETA-SECRETASE INHIBITOR OM00-3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 450 / 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: 2.82 Å3/Da / Density % sol: 56.37 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 22.5% PEG 8000, 0.2 M Ammonium Sulfate, 0.1 M Sodium Cacodylate, pH 6.2, pH 6.5, VAPOR DIFFUSION, HANGING DROP, temperature 293K
Crystal grow
*PLUS
Temperature: 20 ℃ / pH: 6.2
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetails
122.5 %PEG80001reservoir
20.2 Mammonium sulfate1reservoir
30.1 Msodium cacodylate1reservoirpH6.2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.5418 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Apr 15, 2001 / Details: mirrors
RadiationMonochromator: multilayer reflector / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.1→25 Å / Num. all: 59470 / Num. obs: 58812 / % possible obs: 99 % / Redundancy: 3.2 % / Biso Wilson estimate: 23.3 Å2 / Rmerge(I) obs: 0.119 / Net I/σ(I): 7.3
Reflection shellResolution: 2.1→2.18 Å / Mean I/σ(I) obs: 2.2 / % possible all: 97.1
Reflection
*PLUS
Lowest resolution: 25 Å / Num. obs: 58864 / % possible obs: 98.8 % / Num. measured all: 190727
Reflection shell
*PLUS
Highest resolution: 2.1 Å / % possible obs: 97.1 %

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Processing

Software
NameClassification
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
CNSrefinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB Entry 1FKN

1fkn


Resolution: 2.1→25 Å / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflectionSelection details
Rfree0.271 5361 Random
Rwork0.216 --
all-59470 -
obs-58812 -
Displacement parametersBiso mean: 23.1 Å2
Refine analyzeLuzzati coordinate error obs: 0.25 Å / Luzzati d res low obs: 5 Å / Luzzati sigma a obs: 0.28 Å
Refinement stepCycle: LAST / Resolution: 2.1→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6260 0 0 450 6710
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.009
X-RAY DIFFRACTIONc_angle_deg1.6
X-RAY DIFFRACTIONc_dihedral_angle_d25.4
X-RAY DIFFRACTIONc_improper_angle_d0.91
LS refinement shellResolution: 2.1→2.23 Å / Rfactor Rfree error: 0.011
RfactorNum. reflection% reflection
Rfree0.317 812 -
Rwork0.274 --
obs-6957 79.4 %
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg25.4
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg0.91

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