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- PDB-3qbh: Structure based design, synthesis and SAR of cyclic hydroxyethyla... -

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Basic information

Entry
Database: PDB / ID: 3qbh
TitleStructure based design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors
ComponentsBeta-secretase 1
KeywordsHYDROLASE/HYDROLASE Inhibitor / Enzyme inhibitor complex / HYDROLASE / HYDROLASE-HYDROLASE Inhibitor complex
Function / homology
Function and homology information


memapsin 2 / Golgi-associated vesicle lumen / beta-aspartyl-peptidase activity / signaling receptor ligand precursor processing / amyloid-beta formation / amyloid precursor protein catabolic process / membrane protein ectodomain proteolysis / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / prepulse inhibition ...memapsin 2 / Golgi-associated vesicle lumen / beta-aspartyl-peptidase activity / signaling receptor ligand precursor processing / amyloid-beta formation / amyloid precursor protein catabolic process / membrane protein ectodomain proteolysis / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / prepulse inhibition / cellular response to manganese ion / multivesicular body / presynaptic modulation of chemical synaptic transmission / protein serine/threonine kinase binding / cellular response to copper ion / hippocampal mossy fiber to CA3 synapse / trans-Golgi network / recycling endosome / protein processing / response to lead ion / cellular response to amyloid-beta / synaptic vesicle / late endosome / peptidase activity / positive regulation of neuron apoptotic process / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / aspartic-type endopeptidase activity / early endosome / lysosome / endosome / endosome membrane / membrane raft / endoplasmic reticulum lumen / Amyloid fiber formation / axon / neuronal cell body / dendrite / enzyme binding / cell surface / Golgi apparatus / 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-QBH / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.24 Å
AuthorsRondeau, J.M.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Structure based design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors.
Authors: Rueeger, H. / Rondeau, J.M. / McCarthy, C. / Mobitz, H. / Tintelnot-Blomley, M. / Neumann, U. / Desrayaud, S.
#1: Journal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Structure-Based Design 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.
#2: 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.
#3: Journal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Macrocyclic BACE-1 inhibitors acutely reduce Abeta in brain after po application
Authors: Lerchner, A. / Machauer, R. / Betschart, C. / Veenstra, S. / Rueeger, H. / McCarthy, C. / Tintelnot-Blomley, M. / Jaton, A.-L. / Rabe, S. / Desrayaud, S. / Enz, A. / Staufenbiel, M. / ...Authors: Lerchner, A. / Machauer, R. / Betschart, C. / Veenstra, S. / Rueeger, H. / McCarthy, C. / Tintelnot-Blomley, M. / Jaton, A.-L. / Rabe, S. / Desrayaud, S. / Enz, A. / Staufenbiel, M. / Paganetti, P. / Rondeau, J.M. / Neumann, U.
History
DepositionJan 13, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 23, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Mar 1, 2017Group: Other
Revision 1.3Oct 11, 2017Group: Data collection / Refinement description / Category: reflns_shell / software / Item: _reflns_shell.percent_possible_all
Revision 1.4Oct 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
B: Beta-secretase 1
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)135,9666
Polymers134,3323
Non-polymers1,6343
Water9,026501
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,3222
Polymers44,7771
Non-polymers5451
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,3222
Polymers44,7771
Non-polymers5451
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,3222
Polymers44,7771
Non-polymers5451
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)82.003, 103.062, 100.904
Angle α, β, γ (deg.)90.000, 103.980, 90.000
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: 44777.336 Da / Num. of mol.: 3 / Fragment: UNP residues 48-447
Source method: isolated from a genetically manipulated source
Details: Refolded / Source: (gene. exp.) Homo sapiens (human) / Gene: BACE, BACE1, KIAA1149 / Plasmid: pET24 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-QBH / (4S)-4-(2-hydroxy-5-{[(3S,4S,5R)-4-hydroxy-1,1-dioxido-5-{[3-(propan-2-yl)benzyl]amino}tetrahydro-2H-thiopyran-3-yl]methyl}benzyl)-3-propyl-1,3-oxazolidin-2-one


Mass: 544.703 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C29H40N2O6S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 501 / 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: 3.08 Å3/Da / Density % sol: 60.07 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 5
Details: 1.0M Ammonium phosphate, 0.1M sodium citrate pH 5.0, VAPOR DIFFUSION, HANGING DROP, temperature 292K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.97629 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Apr 21, 2005
RadiationMonochromator: SAGITALLY FOCUSED Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97629 Å / Relative weight: 1
ReflectionResolution: 2.24→80 Å / Num. all: 78093 / Num. obs: 78093 / % possible obs: 99.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 7.6 % / Biso Wilson estimate: 48.891 Å2 / Rmerge(I) obs: 0.063 / Net I/σ(I): 18.6
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. unique allNum. unique obs% possible all
2.24-2.337.30.3416631928617861799
2.33-2.47.60.3017450135908590899.9
2.4-2.487.60.2538.2451705919591999.9
2.48-2.567.60.19810.33968351965196100
2.56-2.667.60.163124348356915691100
2.66-2.767.70.13613.9374124882488299.9
2.76-2.887.70.10916.8383855010501099.9
2.88-3.017.70.08719.8350944576457699.9
3.01-3.167.70.07422.93378344104410100
3.16-3.357.70.06425.43410044474447100
3.35-3.567.60.05727.6300823937393799.8
3.56-3.837.60.05628.72912338153815100
3.83-4.167.60.05330.4263733463346399.8
4.16-4.597.60.0531.4238783139313999.8
4.59-5.27.60.04732.92175628652865100
5.2-6.147.60.04833.41882724822482100
6.14-7.877.50.04435.5152972030203099.8
7.87-12.270.03937.192641320132097
12.2-805.50.04232210838638673.5

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
CNSrefinement
PDB_EXTRACT3.1data extraction
XDSdata reduction
CNXphasing
CNXrefinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.24→80 Å / Rfactor Rfree error: 0.002 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.8558 / Data cutoff high absF: 2328977 / 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
Rfree0.219 7814 10 %RANDOM
Rwork0.197 ---
all0.2 78093 --
obs0.2 78093 99.5 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 51.9376 Å2 / ksol: 0.3693 e/Å3
Displacement parametersBiso max: 116.77 Å2 / Biso mean: 48.5611 Å2 / Biso min: 22.7 Å2
Baniso -1Baniso -2Baniso -3
1--2.88 Å20 Å2-0.1 Å2
2--6.86 Å20 Å2
3----3.98 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.29 Å0.26 Å
Luzzati d res low-5 Å
Luzzati sigma a0.26 Å0.2 Å
Refinement stepCycle: LAST / Resolution: 2.24→80 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8867 0 114 501 9482
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.006
X-RAY DIFFRACTIONc_angle_deg1.3
X-RAY DIFFRACTIONc_dihedral_angle_d29.1
X-RAY DIFFRACTIONc_improper_angle_d0.8
X-RAY DIFFRACTIONc_mcbond_it1.941.5
X-RAY DIFFRACTIONc_mcangle_it3.062
X-RAY DIFFRACTIONc_scbond_it2.842
X-RAY DIFFRACTIONc_scangle_it42.5
LS refinement shellResolution: 2.24→2.38 Å / Rfactor Rfree error: 0.002 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.277 1283 10 %
Rwork0.244 11608 -
all-12891 -
obs-12891 99.3 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION3NVP-BGN587.PARAMION.TOP
X-RAY DIFFRACTION4CIS_PEPTIDE.PARAMNVP-BGN587.TOP
X-RAY DIFFRACTION5ION.PARAM

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