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- PDB-1ym2: Crystal structure of human beta secretase complexed with NVP-AUR200 -

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Basic information

Entry
Database: PDB / ID: 1ym2
TitleCrystal structure of human beta secretase complexed with NVP-AUR200
Components
  • Beta-secretase 1
  • NVP-AUR200 INHIBITOR
KeywordsHYDROLASE/HYDROLASE INHIBITOR / BETA-SECRETASE / MEMAPSIN2 / ALZHEIMER'S DISEASE / ASPARTIC PROTEASE / HYDROLASE / 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 / amyloid-beta metabolic process / 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 / cellular response to manganese ion / amyloid-beta metabolic process / 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 / hippocampal mossy fiber to CA3 synapse / multivesicular body / response to lead ion / trans-Golgi network / recycling endosome / protein processing / cellular response to amyloid-beta / positive regulation of neuron apoptotic process / synaptic vesicle / late endosome / peptidase activity / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / aspartic-type endopeptidase activity / lysosome / 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
BETA-SECRETASE INHIBITOR NVP-AUR200 / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.05 Å
AuthorsHanessian, S. / Yun, H. / Hou, Y. / Yang, G. / Bayrakdarian, M. / Therrien, E. / Moitessier, N. / Roggo, S. / Veenstra, S.
CitationJournal: J.Med.Chem. / Year: 2005
Title: Structure-based design, synthesis, and memapsin 2 (BACE) inhibitory activity of carbocyclic and heterocyclic peptidomimetics
Authors: Hanessian, S. / Yun, H. / Hou, Y. / Yang, G. / Bayrakdarian, M. / Therrien, E. / Moitessier, N. / Roggo, S. / Veenstra, S. / Tintelnot-Blomley, M. / Rondeau, J.M. / Ostermeier, C. / Strauss, ...Authors: Hanessian, S. / Yun, H. / Hou, Y. / Yang, G. / Bayrakdarian, M. / Therrien, E. / Moitessier, N. / Roggo, S. / Veenstra, S. / Tintelnot-Blomley, M. / Rondeau, J.M. / Ostermeier, C. / Strauss, A. / Ramage, P. / Paganetti, P. / Neumann, U. / Betschart, C.
History
DepositionJan 20, 2005Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jan 17, 2006Provider: repository / Type: Initial release
Revision 1.1Apr 30, 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 / struct_ref / struct_ref_seq_dif
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 / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_label_atom_id / _struct_ref.pdbx_seq_one_letter_code / _struct_ref_seq_dif.details

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Beta-secretase 1
B: Beta-secretase 1
C: Beta-secretase 1
X: NVP-AUR200 INHIBITOR
Y: NVP-AUR200 INHIBITOR
Z: NVP-AUR200 INHIBITOR


Theoretical massNumber of molelcules
Total (without water)136,3366
Polymers136,3366
Non-polymers00
Water10,413578
1
A: Beta-secretase 1
X: NVP-AUR200 INHIBITOR


Theoretical massNumber of molelcules
Total (without water)45,4452
Polymers45,4452
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1760 Å2
ΔGint-3 kcal/mol
Surface area16050 Å2
MethodPISA
2
B: Beta-secretase 1
Y: NVP-AUR200 INHIBITOR


Theoretical massNumber of molelcules
Total (without water)45,4452
Polymers45,4452
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1840 Å2
ΔGint-2 kcal/mol
Surface area15700 Å2
MethodPISA
3
C: Beta-secretase 1
Z: NVP-AUR200 INHIBITOR


Theoretical massNumber of molelcules
Total (without water)45,4452
Polymers45,4452
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1760 Å2
ΔGint-4 kcal/mol
Surface area15880 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.261, 103.258, 100.621
Angle α, β, γ (deg.)90.00, 104.12, 90.00
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 / Aspartyl ...Beta-site APP cleaving enzyme 1 / Beta-site amyloid precursor protein cleaving enzyme 1 / Aspartyl protease 2 / Asp 2 / ASP2 / Membrane-associated aspartic protease 2 / Memapsin-2


Mass: 44777.336 Da / Num. of mol.: 3 / Fragment: UNP residues 48-447
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pET24 / Production host: Escherichia coli (E. coli) / References: UniProt: P56817, memapsin 2
#2: Protein/peptide NVP-AUR200 INHIBITOR


Type: Peptide-like / Class: Inhibitor / Mass: 667.943 Da / Num. of mol.: 3 / Source method: obtained synthetically / References: BETA-SECRETASE INHIBITOR NVP-AUR200
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 578 / 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: 3.09 Å3/Da / Density % sol: 60 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: Ammonium sulfate, pH 5.5, VAPOR DIFFUSION, HANGING DROP, temperature 292.0K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1.00033 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Jan 28, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00033 Å / Relative weight: 1
ReflectionResolution: 2.05→100 Å / Num. all: 102160 / Num. obs: 102160 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 6.4 % / Biso Wilson estimate: 33.3 Å2 / Rmerge(I) obs: 0.047 / Net I/σ(I): 12.3
Reflection shellResolution: 2.05→2.12 Å / Redundancy: 6.2 % / Rmerge(I) obs: 0.485 / Num. unique all: 9710 / % possible all: 99.8

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Processing

Software
NameVersionClassification
CNX2002refinement
DENZOdata reduction
SCALEPACKdata scaling
CNX2002phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.05→47.05 Å / Rfactor Rfree error: 0.002 / Data cutoff high absF: 16971320.63 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.237 10253 10 %RANDOM
Rwork0.212 ---
all0.215 102108 --
obs0.215 102108 99.7 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 54.3036 Å2 / ksol: 0.35333 e/Å3
Displacement parametersBiso mean: 48.4 Å2
Baniso -1Baniso -2Baniso -3
1-5.02 Å20 Å2-2.66 Å2
2---1.63 Å20 Å2
3----3.39 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.3 Å0.27 Å
Luzzati d res low-5 Å
Luzzati sigma a0.24 Å0.2 Å
Refinement stepCycle: LAST / Resolution: 2.05→47.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9027 0 0 578 9605
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.004
X-RAY DIFFRACTIONc_angle_deg1.2
X-RAY DIFFRACTIONc_dihedral_angle_d25.1
X-RAY DIFFRACTIONc_improper_angle_d0.68
X-RAY DIFFRACTIONc_mcbond_it1.471.5
X-RAY DIFFRACTIONc_mcangle_it2.392
X-RAY DIFFRACTIONc_scbond_it1.932
X-RAY DIFFRACTIONc_scangle_it2.862.5
LS refinement shellResolution: 2.05→2.18 Å / Rfactor Rfree error: 0.007 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.304 1728 10.2 %
Rwork0.278 15176 -
obs-16904 99.8 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION3NVP-AUR200.PARAM
X-RAY DIFFRACTION4CIS_PEPTIDE.PARAM
X-RAY DIFFRACTION5ION.PARAMION.TOP

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