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- PDB-4fsl: Crystal structure of beta-site app-cleaving enzyme 1 (BACE-DB-MUT... -

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Basic information

Entry
Database: PDB / ID: 4fsl
TitleCrystal structure of beta-site app-cleaving enzyme 1 (BACE-DB-MUT) complex with N-(N-(4- acetamido-3-chloro-5-methylbenzyl)carbamimidoyl)-3-(4- methoxyphenyl)-5-methyl-4-isothiazolecarboxamide
ComponentsBeta-secretase 1
KeywordsHYDROLASE/INHIBITOR / ALZHEIMER'S DISEASE / BETA-SECRETASE / MEMAPSIN 2 / BASE / ASPARTIC PROTEASE / 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 / protein processing / recycling endosome / 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
Chem-0VB / IODIDE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.5 Å
AuthorsMuckelbauer, J.K.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Acyl Guanidine Inhibitors of beta-Secretase (BACE-1): Optimization of a Micromolar Hit to a Nanomolar Lead via Iterative Solid- and Solution-Phase Library Synthesis
Authors: Gerritz, S.W. / Zhai, W. / Shi, S. / Zhu, S. / Toyn, J.H. / Meredith, J.E. / Iben, L.G. / Burton, C.R. / Albright, C.F. / Good, A.C. / Tebben, A.J. / Muckelbauer, J.K. / Camac, D.M. / ...Authors: Gerritz, S.W. / Zhai, W. / Shi, S. / Zhu, S. / Toyn, J.H. / Meredith, J.E. / Iben, L.G. / Burton, C.R. / Albright, C.F. / Good, A.C. / Tebben, A.J. / Muckelbauer, J.K. / Camac, D.M. / Metzler, W. / Cook, L.S. / Padmanabha, R. / Lentz, K.A. / Sofia, M.J. / Poss, M.A. / Macor, J.E. / Thompson, L.A.
History
DepositionJun 27, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 10, 2012Provider: repository / Type: Initial release
Revision 1.1Jul 10, 2013Group: Database references
Revision 1.2Nov 15, 2017Group: Refinement description / Category: software / Item: _software.classification / _software.name
Revision 1.3Jun 13, 2018Group: Data collection
Category: diffrn_radiation / diffrn_radiation_wavelength / diffrn_source
Item: _diffrn_radiation.pdbx_diffrn_protocol / _diffrn_radiation.pdbx_monochromatic_or_laue_m_l / _diffrn_source.pdbx_wavelength_list
Revision 1.4Jul 17, 2019Group: Data collection / Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.language / _software.location / _software.name / _software.version

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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
D: Beta-secretase 1
E: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)187,16120
Polymers183,6944
Non-polymers3,46716
Water14,754819
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,7905
Polymers45,9241
Non-polymers8674
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,7905
Polymers45,9241
Non-polymers8674
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
D: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,7905
Polymers45,9241
Non-polymers8674
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
E: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,7905
Polymers45,9241
Non-polymers8674
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)86.540, 131.177, 90.315
Angle α, β, γ (deg.)90.000, 97.610, 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: 45923.547 Da / Num. of mol.: 4 / Fragment: UNP residues 43-453
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BACE1, BACE, KIAA1149 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P56817, memapsin 2
#2: Chemical
ChemComp-0VB / N-{N-[4-(acetylamino)-3-chloro-5-methylbenzyl]carbamimidoyl}-3-(4-methoxyphenyl)-5-methyl-1,2-thiazole-4-carboxamide


Mass: 485.986 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H24ClN5O3S
#3: Chemical
ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: I
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 819 / 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: 2.77 Å3/Da / Density % sol: 55.53 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.2
Details: 35% PEG8K, 0.2 M ammonium sulfate, pH 6.2, vapor diffusion, hanging drop, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.54 / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 92 / Detector: CCD / Date: Apr 29, 2005 / Details: MICROMAX CONFOCAL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionRedundancy: 3.6 % / Av σ(I) over netI: 14.84 / Number: 236790 / Rmerge(I) obs: 0.087 / Χ2: 1.12 / D res high: 2.5 Å / D res low: 50 Å / Num. obs: 66645 / % possible obs: 96.8
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)% possible obs (%)IDRmerge(I) obsChi squaredRedundancy
5.385099.310.0481.3233.7
4.275.3899.310.0471.1633.8
3.734.2798.910.0551.1163.8
3.393.7398.610.0741.1753.8
3.153.3998.310.1091.0613.7
2.963.1597.610.161.1093.5
2.822.9696.510.2151.0613.4
2.692.8295.410.2821.0643.3
2.592.699310.3541.0363.2
2.52.5991.110.4721.0513.2
ReflectionResolution: 2.5→50 Å / Num. obs: 66645 / % possible obs: 96.8 % / Redundancy: 3.6 % / Rmerge(I) obs: 0.087 / Χ2: 1.123 / Net I/σ(I): 7.7
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.5-2.593.20.47262441.051191.1
2.59-2.693.20.35463851.036193
2.69-2.823.30.28265361.064195.4
2.82-2.963.40.21566521.061196.5
2.96-3.153.50.1666651.109197.6
3.15-3.393.70.10967381.061198.3
3.39-3.733.80.07468121.175198.6
3.73-4.273.80.05568081.116198.9
4.27-5.383.80.04768571.163199.3
5.38-503.70.04869481.323199.3

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
REFMAC5.2.0019refinement
SCALEPACKdata scaling
CNSrefinement
DENZOdata reduction
PDB_EXTRACT3.11data extraction
HKL-2000data reduction
HKL-2000data scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→50 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.902 / Occupancy max: 1 / Occupancy min: 1 / SU B: 9.853 / SU ML: 0.218 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.639 / ESU R Free: 0.325 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.277 3377 5.1 %RANDOM
Rwork0.2239 ---
obs0.2265 66542 96.54 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 142.43 Å2 / Biso mean: 26.3625 Å2 / Biso min: 2.25 Å2
Baniso -1Baniso -2Baniso -3
1--2.52 Å20 Å20.52 Å2
2---1.86 Å20 Å2
3---4.51 Å2
Refinement stepCycle: LAST / Resolution: 2.5→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12156 0 144 819 13119
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.02212619
X-RAY DIFFRACTIONr_angle_refined_deg1.1541.95817174
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.61251544
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.08623.958576
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.724151976
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.3271568
X-RAY DIFFRACTIONr_chiral_restr0.0690.21848
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.029784
X-RAY DIFFRACTIONr_nbd_refined0.1790.25905
X-RAY DIFFRACTIONr_nbtor_refined0.3050.28558
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1250.21070
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2220.2101
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0990.222
X-RAY DIFFRACTIONr_mcbond_it0.3181.57715
X-RAY DIFFRACTIONr_mcangle_it0.589212419
X-RAY DIFFRACTIONr_scbond_it0.62335572
X-RAY DIFFRACTIONr_scangle_it1.0734.54755
LS refinement shellHighest resolution: 2.502 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.359 246 -
Rwork0.297 4284 -
all-4530 -
obs--88.77 %

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