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- PDB-4b05: Preclinical characterization of AZD3839, a novel clinical candida... -

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Entry
Database: PDB / ID: 4b05
TitlePreclinical characterization of AZD3839, a novel clinical candidate BACE1 inhibitor for the treatment of Alzheimer Disease
ComponentsBETA-SECRETASE 1
KeywordsHYDROLASE / AMINOISOINDOLE / ALZHEIMER'S DISEASE
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
Chem-32D / ACETATE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsJeppsson, F. / Eketjall, S. / Janson, J. / Karlstrom, S. / Gustavsson, S. / Olsson, L.L. / Radesater, A.C. / Ploeger, B. / Cebers, G. / Kolmodin, K. ...Jeppsson, F. / Eketjall, S. / Janson, J. / Karlstrom, S. / Gustavsson, S. / Olsson, L.L. / Radesater, A.C. / Ploeger, B. / Cebers, G. / Kolmodin, K. / Swahn, B.M. / von Berg, S. / Bueters, T. / Falting, J.
CitationJournal: J. Biol. Chem. / Year: 2012
Title: Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer disease.
Authors: Jeppsson, F. / Eketjall, S. / Janson, J. / Karlstrom, S. / Gustavsson, S. / Olsson, L.L. / Radesater, A.C. / Ploeger, B. / Cebers, G. / Kolmodin, K. / Swahn, B.M. / von Berg, S. / Bueters, T. / Falting, J.
History
DepositionJun 28, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 17, 2012Provider: repository / Type: Initial release
Revision 1.1Oct 24, 2012Group: Database references
Revision 1.2Dec 12, 2012Group: Database references
Revision 1.3Dec 19, 2012Group: Database references / Refinement description
Revision 1.4Feb 14, 2018Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.title / _citation_author.name
Revision 1.5May 1, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / 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 / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.6Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: BETA-SECRETASE 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,5728
Polymers45,8221
Non-polymers7507
Water6,413356
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)47.529, 76.533, 104.161
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 / BETA-SITE AMYLOID PRECURSOR PROTEIN CLEAVING ENZYME 1 / BETA-SITE APP ...ASPARTYL PROTEASE 2 / ASP2 / BETA-SITE AMYLOID PRECURSOR PROTEIN CLEAVING ENZYME 1 / BETA-SITE APP CLEAVING ENZYME 1 / MEMAPSIN-2 / MEMBRANE-ASSOCIATED ASPARTIC PROTEASE 2


Mass: 45822.445 Da / Num. of mol.: 1 / Fragment: RESIDUES 43-453 / Mutation: YES
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-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H3O2
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#4: Chemical ChemComp-32D / (1S)-1-[2-(difluoromethyl)pyridin-4-yl]-4-fluoro-1-(3-pyrimidin-5-ylphenyl)-1H-isoindol-3-amine


Mass: 431.413 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H16F3N5
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 356 / Source method: isolated from a natural source / Formula: H2O
Compound detailsENGINEERED RESIDUE IN CHAIN A, ARG 56 TO LYS ENGINEERED RESIDUE IN CHAIN A, ARG 57 TO LYS
Has protein modificationY
Sequence detailsPROPEPTIDE NUMBERED 484-502

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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: 2.05 Å3/Da / Density % sol: 40 % / Description: NONE
Crystal growpH: 5
Details: 11% PEG6K, 90 MM NAAC PH 5.0, 18 MM TRIS PH 8.5, 135 MM NACL

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E / Wavelength: 1.5418
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Mar 2, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.8→26.3 Å / Num. obs: 35173 / % possible obs: 97.9 % / Observed criterion σ(I): 0 / Redundancy: 3.4 % / Biso Wilson estimate: 24.01 Å2 / Rmerge(I) obs: 0.05 / Net I/σ(I): 20.8
Reflection shellResolution: 1.8→1.85 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.49 / Mean I/σ(I) obs: 2.3 / % possible all: 94.1

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Processing

Software
NameVersionClassification
BUSTER2.11.1refinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PREVIOUSLY SOLVED IN-HOUSE BACE1 STRUCTURE

Resolution: 1.8→26.33 Å / Cor.coef. Fo:Fc: 0.9469 / Cor.coef. Fo:Fc free: 0.928 / SU R Cruickshank DPI: 0.126 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.135 / SU Rfree Blow DPI: 0.124 / SU Rfree Cruickshank DPI: 0.12
Details: REFINEMENT NOTE 1: IDEAL-DIST CONTACT SETUP. RESIDUE TYPES WITHOUT CCP4 ATOM TYPE IN LIBRARY= NA NUMBER TYPES WITHOUT CCP4 ATOM TYPE IN LIBRARY=NA. NUMBER OF ATOM WITH PROPER CCP4 ATOM ...Details: REFINEMENT NOTE 1: IDEAL-DIST CONTACT SETUP. RESIDUE TYPES WITHOUT CCP4 ATOM TYPE IN LIBRARY= NA NUMBER TYPES WITHOUT CCP4 ATOM TYPE IN LIBRARY=NA. NUMBER OF ATOM WITH PROPER CCP4 ATOM TYPE=3329. NUMBER WITH APPROX DEFAULT CCP4 ATOM TYPE=0. NUMBER TREATED BY BAD NON-BONDED CONTACTS=1.
RfactorNum. reflection% reflectionSelection details
Rfree0.2152 1761 5 %RANDOM
Rwork0.1777 ---
obs0.1796 35128 97.6 %-
Displacement parametersBiso mean: 26.92 Å2
Baniso -1Baniso -2Baniso -3
1--6.9132 Å20 Å20 Å2
2--1.6459 Å20 Å2
3---5.2673 Å2
Refine analyzeLuzzati coordinate error obs: 0.197 Å
Refinement stepCycle: LAST / Resolution: 1.8→26.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2921 0 53 356 3330
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.013046HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.134132HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1006SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes74HARMONIC2
X-RAY DIFFRACTIONt_gen_planes451HARMONIC5
X-RAY DIFFRACTIONt_it3046HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.97
X-RAY DIFFRACTIONt_other_torsion15.7
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion383SEMIHARMONIC5
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_contact3669SEMIHARMONIC4
LS refinement shellResolution: 1.8→1.85 Å / Total num. of bins used: 18
RfactorNum. reflection% reflection
Rfree0.3543 128 4.72 %
Rwork0.3401 2584 -
all0.3408 2712 -
obs--97.63 %

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