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- PDB-4fse: crystal structure of beta-site app-cleaving enzyme 1 (bace-wt) co... -

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Basic information

Entry
Database: PDB / ID: 4fse
Titlecrystal structure of beta-site app-cleaving enzyme 1 (bace-wt) complex with N-(N-(4-amino-3,5- dichlorobenzyl)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 / prepulse inhibition / amyloid-beta metabolic process ...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 / prepulse inhibition / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / cellular response to copper ion / hippocampal mossy fiber to CA3 synapse / presynaptic modulation of chemical synaptic transmission / 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 / amyloid-beta binding / peptidase activity / endopeptidase activity / amyloid fibril formation / lysosome / aspartic-type endopeptidase activity / early endosome / endosome membrane / endosome / membrane raft / Amyloid fiber formation / axon / endoplasmic reticulum lumen / dendrite / neuronal cell body / 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-0VA / IODIDE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.65 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 1.2Jun 13, 2018Group: Data collection
Category: diffrn_radiation / diffrn_radiation_wavelength / diffrn_source
Item: _diffrn_radiation.pdbx_monochromatic_or_laue_m_l / _diffrn_source.pdbx_wavelength_list
Revision 1.3Jul 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)203,88217
Polymers200,8824
Non-polymers3,00013
Water7,837435
1
A: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,9394
Polymers50,2201
Non-polymers7183
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,9394
Polymers50,2201
Non-polymers7183
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
D: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,9394
Polymers50,2201
Non-polymers7183
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
E: Beta-secretase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,0665
Polymers50,2201
Non-polymers8454
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)86.334, 131.219, 88.947
Angle α, β, γ (deg.)90.000, 97.600, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
31D
41E

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1112A-5 - 385
2112B-5 - 385
3112D-5 - 385
4112E-5 - 385

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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: 50220.492 Da / Num. of mol.: 4 / Fragment: UNP residues 14-454
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-0VA / N-[N-(4-amino-3,5-dichlorobenzyl)carbamimidoyl]-3-(4-methoxyphenyl)-5-methyl-1,2-thiazole-4-carboxamide


Mass: 464.368 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H19Cl2N5O2S
#3: Chemical
ChemComp-IOD / IODIDE ION / Iodide


Mass: 126.904 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: I
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 435 / 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: 2.49 Å3/Da / Density % sol: 50.52 %
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
ReflectionResolution: 2.65→50 Å / Num. obs: 56952 / % possible obs: 99.8 % / Redundancy: 3.7 % / Rmerge(I) obs: 0.135 / Χ2: 1.07 / Net I/σ(I): 5.5
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.65-2.743.50.4956191.042199
2.74-2.853.60.42756851.072199.6
2.85-2.983.60.3356561.053199.9
2.98-3.143.70.25856651.0491100
3.14-3.343.70.18557021.0231100
3.34-3.63.70.12756961.041100
3.6-3.963.80.09357031.0681100
3.96-4.533.70.07557101.0661100
4.53-5.713.70.07157181.0871100
5.71-503.60.06657981.195199.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
REFMAC5.2.0019refinement
CNSrefinement
SCALEPACKdata scaling
PDB_EXTRACT3.11data extraction
StructureStudiodata collection
HKL-2000data reduction
HKL-2000data scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.65→44.08 Å / Cor.coef. Fo:Fc: 0.926 / Cor.coef. Fo:Fc free: 0.887 / Occupancy max: 1 / Occupancy min: 1 / SU B: 11.965 / SU ML: 0.249 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 1.167 / ESU R Free: 0.349 / Stereochemistry target values: Engh & Huber / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2669 2884 5.1 %RANDOM
Rwork0.2171 ---
obs0.2196 56926 99.76 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 500 Å2 / Biso mean: 20.8044 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1--1.67 Å20 Å20.16 Å2
2---1.62 Å20 Å2
3---3.33 Å2
Refinement stepCycle: LAST / Resolution: 2.65→44.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12146 0 129 435 12710
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.02212598
X-RAY DIFFRACTIONr_angle_refined_deg1.3641.95717146
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.92751544
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.29723.927573
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.56151973
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.0991568
X-RAY DIFFRACTIONr_chiral_restr0.0910.21875
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.029744
X-RAY DIFFRACTIONr_nbd_refined0.1940.25725
X-RAY DIFFRACTIONr_nbtor_refined0.3090.28509
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1530.2715
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2880.276
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1920.210
X-RAY DIFFRACTIONr_mcbond_it0.4311.57722
X-RAY DIFFRACTIONr_mcangle_it0.8212415
X-RAY DIFFRACTIONr_scbond_it0.93535560
X-RAY DIFFRACTIONr_scangle_it1.5624.54731
Refine LS restraints NCS

Dom-ID: 1 / Ens-ID: 1 / Refine-ID: X-RAY DIFFRACTION

Auth asym-IDNumberTypeRms dev position (Å)Weight position
A1544TIGHT POSITIONAL0.030.05
B1544TIGHT POSITIONAL0.030.05
D1544TIGHT POSITIONAL0.030.05
E1544TIGHT POSITIONAL0.030.05
A1477MEDIUM POSITIONAL0.370.5
B1477MEDIUM POSITIONAL0.40.5
D1477MEDIUM POSITIONAL0.370.5
E1477MEDIUM POSITIONAL0.350.5
A1544TIGHT THERMAL0.040.5
B1544TIGHT THERMAL0.050.5
D1544TIGHT THERMAL0.050.5
E1544TIGHT THERMAL0.040.5
A1477MEDIUM THERMAL0.312
B1477MEDIUM THERMAL0.372
D1477MEDIUM THERMAL0.362
E1477MEDIUM THERMAL0.332
LS refinement shellHighest resolution: 2.65 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.317 206 -
Rwork0.288 3910 -
all-4116 -
obs--98.19 %

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