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- PDB-3dv1: Crystal structure of human beta-secretase in complex with NVP-ARV999 -

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Basic information

Entry
Database: PDB / ID: 3dv1
TitleCrystal structure of human beta-secretase in complex with NVP-ARV999
ComponentsBeta-secretase 1
KeywordsHYDROLASE / beta-secretase / Bace1 / Memapsin2 / Aspartic protease / Enzyme inhibitor complex / Alzheimer's disease / Alternative splicing / Aspartyl protease / Glycoprotein / Membrane / 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 / amyloid-beta metabolic process / cellular response to manganese ion / 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 / amyloid-beta metabolic process / cellular response to manganese ion / prepulse inhibition / detection of mechanical stimulus involved in sensory perception of pain / 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 / 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 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-AR9 / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.1 Å
AuthorsRondeau, J.-M.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Macrocyclic peptidomimetic beta-secretase (BACE-1) inhibitors with activity in vivo.
Authors: Machauer, R. / Laumen, K. / Veenstra, S. / Rondeau, J.M. / Tintelnot-Blomley, M. / Betschart, C. / Jaton, A.L. / Desrayaud, S. / Staufenbiel, M. / Rabe, S. / Paganetti, P. / Neumann, U.
#1: Journal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Structure-based design and synthesis of macrocyclic peptidomimetic beta-secretase (BACE-1) inhibitors.
Authors: Machauer, R. / Veenstra, S. / Rondeau, J.M. / Tintelnot-Blomley, M. / Betschart, C. / Neumann, U. / Paganetti, P.
History
DepositionJul 18, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 24, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 25, 2017Group: Refinement description / Category: software
Revision 1.3Aug 30, 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 1.4Oct 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
B: Beta-secretase 1
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)135,6516
Polymers134,3323
Non-polymers1,3193
Water9,458525
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,2172
Polymers44,7771
Non-polymers4401
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,2172
Polymers44,7771
Non-polymers4401
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,2172
Polymers44,7771
Non-polymers4401
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)82.027, 102.945, 99.916
Angle α, β, γ (deg.)90.000, 103.660, 90.000
Int Tables number4
Space group name H-MP1211

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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: 44777.336 Da / Num. of mol.: 3 / Fragment: Catalytic domain: Residues 48-447
Source method: isolated from a genetically manipulated source
Details: Refolded / Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE / Plasmid: pET24 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-AR9 / (2R,4S)-N-butyl-4-[(2S,5S,7R)-2,7-dimethyl-3,15-dioxo-1,4-diazacyclopentadecan-5-yl]-4-hydroxy-2-methylbutanamide / (2R,4S)-N-Butyl-4-((2S,5S,7R)-2,7-dimethyl-3,15-dioxo-1,4diaza-cyclopentadec-5-yl)-4-hydroxy-2-methyl-butyramide


Mass: 439.632 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C24H45N3O4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 525 / 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: 3.05 Å3/Da / Density % sol: 59.69 %
Crystal growDetails: 1.0M Ammonium sulfate in water, pH 5.5, VAPOR DIFFUSION, SITTING DROP, temperature 292K. Protein stock was BACE 7.3 mg/mL in 10mM Tris-HCl pH 7.4, 25mM NaCl. Crystals were grown in 96-well ...Details: 1.0M Ammonium sulfate in water, pH 5.5, VAPOR DIFFUSION, SITTING DROP, temperature 292K. Protein stock was BACE 7.3 mg/mL in 10mM Tris-HCl pH 7.4, 25mM NaCl. Crystals were grown in 96-well Corning Microtiter plates. Cryo-protectant was 80% well solution, 20% 1,2-Propanediol

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Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.95371 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Mar 27, 2003
RadiationMonochromator: SAGITALLY FOCUSED Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.95371 Å / Relative weight: 1
ReflectionResolution: 2.1→100 Å / Num. all: 93176 / Num. obs: 93176 / % possible obs: 100 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 4.3 % / Biso Wilson estimate: 30.8 Å2 / Rmerge(I) obs: 0.056 / Χ2: 1.004 / Net I/σ(I): 12.1
Reflection shellResolution: 2.1→2.18 Å / Rmerge(I) obs: 0.309 / Num. unique all: 9252 / Χ2: 0.47 / % possible all: 100

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACT3.006data extraction
MAR345CCDdata collection
CNXphasing
CNXrefinement
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB entry 3DUY

3duy


Resolution: 2.1→55.52 Å / Rfactor Rfree error: 0.002 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.829 / Data cutoff high absF: 17397696 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.241 9307 10 %RANDOM
Rwork0.207 ---
all0.223 93153 --
obs0.223 93153 99.4 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 53.539 Å2 / ksol: 0.344 e/Å3
Displacement parametersBiso max: 125.07 Å2 / Biso mean: 46.843 Å2 / Biso min: 20.28 Å2
Baniso -1Baniso -2Baniso -3
1--2.89 Å20 Å21.51 Å2
2--4.37 Å20 Å2
3----1.48 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.3 Å0.26 Å
Luzzati d res low-5 Å
Luzzati sigma a0.23 Å0.17 Å
Refinement stepCycle: LAST / Resolution: 2.1→55.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8934 0 93 525 9552
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.005
X-RAY DIFFRACTIONc_angle_deg1.3
X-RAY DIFFRACTIONc_dihedral_angle_d25
X-RAY DIFFRACTIONc_improper_angle_d0.76
X-RAY DIFFRACTIONc_mcbond_it2.181.5
X-RAY DIFFRACTIONc_mcangle_it3.262
X-RAY DIFFRACTIONc_scbond_it3.052
X-RAY DIFFRACTIONc_scangle_it4.252.5
LS refinement shellResolution: 2.1→2.23 Å / Rfactor Rfree error: 0.008 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.287 1429 9.7 %
Rwork0.248 13233 -
all-14662 -
obs-14732 94.2 %

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