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- PDB-4rrn: 8-Tetrahydropyran-2-yl chromans: highly selective beta-site amylo... -

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Basic information

Entry
Database: PDB / ID: 4rrn
Title8-Tetrahydropyran-2-yl chromans: highly selective beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors
ComponentsBeta-secretase 1
Keywordshydrolase/hydrolase inhibitor / Aspartyl 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-3UW / NICKEL (II) ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsThomas, A.A. / Hunt, K.W. / Newhouse, B. / Watts, R.J. / Liu, X. / Vigers, G.P.A. / Smith, D. / Rhodes, S.P. / Brown, K.D. / Otten, J.N. ...Thomas, A.A. / Hunt, K.W. / Newhouse, B. / Watts, R.J. / Liu, X. / Vigers, G.P.A. / Smith, D. / Rhodes, S.P. / Brown, K.D. / Otten, J.N. / Burkard, M. / Cox, A.A. / Geck Do, M.K. / Dutcher, D. / Rana, S. / DeLisle, R.K. / Regal, K. / Wright, A.D. / Groneberg, R. / Liao, J. / Scearce-Levie, K. / Siu, M. / Purkey, H.E. / Lyssikatos, J.P.
CitationJournal: J.Med.Chem. / Year: 2014
Title: 8-Tetrahydropyran-2-yl Chromans: Highly Selective Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors.
Authors: Thomas, A.A. / Hunt, K.W. / Newhouse, B. / Watts, R.J. / Liu, X. / Vigers, G. / Smith, D. / Rhodes, S.P. / Brown, K.D. / Otten, J.N. / Burkard, M. / Cox, A.A. / Geck Do, M.K. / Dutcher, D. / ...Authors: Thomas, A.A. / Hunt, K.W. / Newhouse, B. / Watts, R.J. / Liu, X. / Vigers, G. / Smith, D. / Rhodes, S.P. / Brown, K.D. / Otten, J.N. / Burkard, M. / Cox, A.A. / Geck Do, M.K. / Dutcher, D. / Rana, S. / DeLisle, R.K. / Regal, K. / Wright, A.D. / Groneberg, R. / Liao, J. / Scearce-Levie, K. / Siu, M. / Purkey, H.E. / Lyssikatos, J.P.
History
DepositionNov 6, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 3, 2014Provider: repository / Type: Initial release
Revision 1.1Dec 31, 2014Group: 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_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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,8863
Polymers45,4451
Non-polymers4412
Water5,549308
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)75.470, 103.840, 100.300
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-707-

HOH

21A-761-

HOH

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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: 45445.121 Da / Num. of mol.: 1 / Fragment: unp residues 57-453
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE, BACE1, KIAA1149 / Production host: Escherichia coli (E. coli) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-NI / NICKEL (II) ION


Mass: 58.693 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ni
#3: Chemical ChemComp-3UW / (4S,4a'S,10a'R)-2-amino-8'-(2-fluoropyridin-3-yl)-1-methyl-3',4',4a',10a'-tetrahydro-2'H-spiro[imidazole-4,10'-pyrano[3,2-b]chromen]-5(1H)-one


Mass: 382.388 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H19FN4O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 308 / 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: 2.16 Å3/Da / Density % sol: 43.11 %
Crystal growTemperature: 279 K / Method: vapor diffusion, hanging drop / pH: 4.5
Details: 16% PEG3K, 0.1M NaAcetate pH 4.5, 5% DMSO, VAPOR DIFFUSION, HANGING DROP, temperature 279K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: May 17, 2011 / Details: Confocal mirrors
RadiationMonochromator: Confocal mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.8→30 Å / Num. all: 36713 / Num. obs: 35040 / % possible obs: 95.4 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 6.9 % / Rmerge(I) obs: 0.057 / Rsym value: 0.052 / Net I/σ(I): 15.3
Reflection shellResolution: 1.8→1.9 Å / Redundancy: 4.8 % / Rmerge(I) obs: 0.117 / Mean I/σ(I) obs: 7.3 / Num. unique all: 5225 / Rsym value: 0.117 / % possible all: 74.8

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPphasing
REFMAC5.8.0049refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→29.2 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.933 / SU B: 2.439 / SU ML: 0.078 / Cross valid method: THROUGHOUT / ESU R: 0.147 / ESU R Free: 0.131 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2184 1756 5 %RANDOM
Rwork0.18791 ---
obs0.18946 33254 95.04 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 29.297 Å2
Baniso -1Baniso -2Baniso -3
1--0.18 Å2-0 Å20 Å2
2---0.93 Å20 Å2
3---1.11 Å2
Refinement stepCycle: LAST / Resolution: 1.8→29.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3101 0 29 308 3438
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0193216
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.1151.9534379
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0655391
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.04123.826149
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.58915507
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.791518
X-RAY DIFFRACTIONr_chiral_restr0.0770.2471
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212476
X-RAY DIFFRACTIONr_gen_planes_other
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_it1.1762.7491570
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.0134.1151959
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.4712.9341643
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined4.99924.0935187
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.298 82 -
Rwork0.208 1717 -
obs--67.28 %

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