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- PDB-4b0q: Lead Generation of BACE1 Inhibitors by Coupling Non-amidine New W... -

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Basic information

Entry
Database: PDB / ID: 4b0q
TitleLead Generation of BACE1 Inhibitors by Coupling Non-amidine New Warheads to a Known Binding Scaffold
ComponentsBETA-SECRETASE 1
KeywordsHYDROLASE / BACE1 INHIBITORS / LEAD GENERATION / STRUCTURE-BASED DRUG DESIGN
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 / amyloid-beta metabolic process / cellular response to manganese ion / 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 / amyloid-beta metabolic process / cellular response to manganese ion / 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 / multivesicular body / hippocampal mossy fiber to CA3 synapse / response to lead ion / trans-Golgi network / recycling endosome / protein processing / cellular response to amyloid-beta / positive regulation of neuron apoptotic process / late endosome / synaptic vesicle / peptidase activity / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / aspartic-type endopeptidase activity / early endosome / lysosome / 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
ACETATE ION / Chem-GMF / Beta-secretase 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.87 Å
AuthorsPendrill, R. / Kolmodin, K. / Johansson, P. / Plobeck, N.
CitationJournal: To be Published
Title: Lead Generation of Bace1 Inhibitors by Coupling Non-Amidine New Warheads to a Known Binding Scaffold
Authors: Pendrill, R. / Kolmodin, K. / Johansson, P. / Plobeck, N.
History
DepositionJul 4, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 24, 2013Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / 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 / _pdbx_database_status.status_code_sf / _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)43,3185
Polymers42,8081
Non-polymers5104
Water5,765320
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)47.571, 76.277, 103.939
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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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: 42808.273 Da / Num. of mol.: 1 / Fragment: RESIDUES 62-445
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P56817, memapsin 2
#2: Chemical ChemComp-GMF / 2-[[3-(3-methoxyphenyl)phenyl]-(4-pyridyl)methyl]guanidine


Mass: 332.399 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H20N4O
#3: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H3O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 320 / 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: 2.3 Å3/Da / Density % sol: 46 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Wavelength: 1.5418
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Jul 1, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.87→43.27 Å / Num. obs: 31727 / % possible obs: 99.1 % / Observed criterion σ(I): 2 / Redundancy: 3.2 % / Biso Wilson estimate: 21.4 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 12.5
Reflection shellResolution: 1.87→1.92 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.39 / Mean I/σ(I) obs: 2.6 / % possible all: 93.5

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Processing

Software
NameVersionClassification
BUSTER2.11.1refinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.87→24.02 Å / Cor.coef. Fo:Fc: 0.9445 / Cor.coef. Fo:Fc free: 0.912 / SU R Cruickshank DPI: 0.144 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.155 / SU Rfree Blow DPI: 0.143 / SU Rfree Cruickshank DPI: 0.138
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2245 1557 5.05 %RANDOM
Rwork0.1773 ---
obs0.1797 30808 96.28 %-
Displacement parametersBiso mean: 24.38 Å2
Baniso -1Baniso -2Baniso -3
1--2.3742 Å20 Å20 Å2
2--1.4427 Å20 Å2
3---0.9315 Å2
Refine analyzeLuzzati coordinate error obs: 0.192 Å
Refinement stepCycle: LAST / Resolution: 1.87→24.02 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2907 0 37 320 3264
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.013023HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.134107HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1005SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes72HARMONIC2
X-RAY DIFFRACTIONt_gen_planes449HARMONIC5
X-RAY DIFFRACTIONt_it3023HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion4.03
X-RAY DIFFRACTIONt_other_torsion16.31
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion384SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3654SEMIHARMONIC4
LS refinement shellResolution: 1.87→1.94 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.2924 128 4.7 %
Rwork0.2442 2596 -
all0.2464 2724 -
obs--96.28 %

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