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- PDB-4k9h: Bace-1 inhibitor complex -

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Basic information

Entry
Database: PDB / ID: 4k9h
TitleBace-1 inhibitor complex
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / aspartic protease / 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 / detection of mechanical stimulus involved in sensory perception of pain / amyloid-beta metabolic process / cellular response to manganese ion ...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 / detection of mechanical stimulus involved in sensory perception of pain / amyloid-beta metabolic process / cellular response to manganese ion / prepulse inhibition / 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 / positive regulation of neuron apoptotic process / cellular response to amyloid-beta / late endosome / synaptic vesicle / peptidase activity / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / lysosome / aspartic-type endopeptidase activity / 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
Chem-1QU / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.29 Å
AuthorsJordan, S.R.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Hydroxyethylamine-based inhibitors of BACE1: P1-P3 macrocyclization can improve potency, selectivity, and cell activity.
Authors: Pennington, L.D. / Whittington, D.A. / Bartberger, M.D. / Jordan, S.R. / Monenschein, H. / Nguyen, T.T. / Yang, B.H. / Xue, Q.M. / Vounatsos, F. / Wahl, R.C. / Chen, K. / Wood, S. / Citron, ...Authors: Pennington, L.D. / Whittington, D.A. / Bartberger, M.D. / Jordan, S.R. / Monenschein, H. / Nguyen, T.T. / Yang, B.H. / Xue, Q.M. / Vounatsos, F. / Wahl, R.C. / Chen, K. / Wood, S. / Citron, M. / Patel, V.F. / Hitchcock, S.A. / Zhong, W.
History
DepositionApr 19, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 10, 2013Provider: repository / Type: Initial release
Revision 1.1Jul 17, 2013Group: Database references
Revision 1.2Oct 30, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)131,5996
Polymers129,7673
Non-polymers1,8323
Water1448
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,8662
Polymers43,2561
Non-polymers6111
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,8662
Polymers43,2561
Non-polymers6111
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,8662
Polymers43,2561
Non-polymers6111
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)82.538, 103.304, 100.856
Angle α, β, γ (deg.)90.00, 104.01, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Beta-secretase 1 / Aspartyl protease 2 / ASP2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta- ...Aspartyl protease 2 / ASP2 / Asp 2 / Beta-site amyloid precursor protein cleaving enzyme 1 / Beta-site APP cleaving enzyme 1 / Memapsin-2 / Membrane-associated aspartic protease 2


Mass: 43255.754 Da / Num. of mol.: 3 / Fragment: UNP residues 59-446
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149 / Production host: Escherichia coli (E. coli) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-1QU / 1-cyclopentyl-N-[(2S,3R)-3-hydroxy-1-phenyl-4-{[3-(trifluoromethyl)benzyl]amino}butan-2-yl]-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide / N-((1S,2R)-1-benzyl-2-hydroxy-3-((3-trifluoromethyl)benzyl)amino)propyl)-1-cyclopentyl-6-oxo-5-(2-oxo-1-pyrrolidinyl)-1,6-dihydro-3-pyridinecarboxamide


Mass: 610.666 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C33H37F3N4O4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 8 / 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: 3.21 Å3/Da / Density % sol: 61.74 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6.8
Details: Vapor diffusion - 1 ul protein at 15mg/ml added to 1 ul well buffer, 1.7M NaH2PO4 and 0.91 M K2HPO4., pH 6.8, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Aug 15, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.29→44 Å / Num. obs: 73438 / % possible obs: 87.5 % / Observed criterion σ(F): 2 / Rmerge(I) obs: 0.081

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
X-PLORmodel building
REFMAC5.7.0032refinement
DENZOdata reduction
SCALEPACKdata scaling
X-PLORphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.29→44 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.932 / SU B: 6.487 / SU ML: 0.156 / Cross valid method: THROUGHOUT / ESU R: 0.257 / ESU R Free: 0.217 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24831 3511 5.1 %RANDOM
Rwork0.19928 ---
obs0.20176 65853 94.41 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 46.342 Å2
Baniso -1Baniso -2Baniso -3
1-0.1 Å2-0 Å20.07 Å2
2---0.04 Å20 Å2
3----0.07 Å2
Refinement stepCycle: LAST / Resolution: 2.29→44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8739 0 132 8 8879
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0199114
X-RAY DIFFRACTIONr_bond_other_d0.0010.028441
X-RAY DIFFRACTIONr_angle_refined_deg1.961.96112394
X-RAY DIFFRACTIONr_angle_other_deg0.9133.00419247
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.7151100
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.63323.723411
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.125151430
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.5441551
X-RAY DIFFRACTIONr_chiral_restr0.1280.21337
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.02110292
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022144
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.295→2.354 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.381 240 -
Rwork0.316 4438 -
obs--87.39 %

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