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- PDB-4azy: Design and Synthesis of BACE1 Inhibitors with In Vivo Brain Reduc... -

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Entry
Database: PDB / ID: 4azy
TitleDesign and Synthesis of BACE1 Inhibitors with In Vivo Brain Reduction of beta-Amyloid Peptides (COMPOUND 10)
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-7F3 / ACETATE ION / Beta-secretase 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.79 Å
AuthorsSwahn, B.M. / Kolmodin, K. / Karlstrom, S. / von Berg, S. / Soderman, P. / Holenz, J. / Berg, S. / Lindstrom, J. / Sundstrom, M. / Turek, D. ...Swahn, B.M. / Kolmodin, K. / Karlstrom, S. / von Berg, S. / Soderman, P. / Holenz, J. / Berg, S. / Lindstrom, J. / Sundstrom, M. / Turek, D. / Kihlstrom, J. / Slivo, C. / Andersson, L. / Pyring, D. / Ohberg, L. / Kers, A. / Bogar, K. / Bergh, M. / Olsson, L.L. / Janson, J. / Eketjall, S. / Georgievska, B. / Jeppsson, F. / Falting, J.
CitationJournal: J. Med. Chem. / Year: 2012
Title: Design and synthesis of beta-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors with in vivo brain reduction of beta-amyloid peptides.
Authors: Swahn, B.M. / Kolmodin, K. / Karlstrom, S. / von Berg, S. / Soderman, P. / Holenz, J. / Berg, S. / Lindstrom, J. / Sundstrom, M. / Turek, D. / Kihlstrom, J. / Slivo, C. / Andersson, L. / ...Authors: Swahn, B.M. / Kolmodin, K. / Karlstrom, S. / von Berg, S. / Soderman, P. / Holenz, J. / Berg, S. / Lindstrom, J. / Sundstrom, M. / Turek, D. / Kihlstrom, J. / Slivo, C. / Andersson, L. / Pyring, D. / Rotticci, D. / Ohberg, L. / Kers, A. / Bogar, K. / von Kieseritzky, F. / Bergh, M. / Olsson, L.L. / Janson, J. / Eketjall, S. / Georgievska, B. / Jeppsson, F. / Falting, J.
History
DepositionJun 27, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 17, 2012Provider: repository / Type: Initial release
Revision 1.1Nov 21, 2012Group: Database references
Revision 1.2Feb 14, 2018Group: Database references / Structure summary / Category: audit_author / citation / citation_author
Item: _audit_author.name / _citation.journal_abbrev ..._audit_author.name / _citation.journal_abbrev / _citation.journal_id_ISSN / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.title / _citation_author.name
Revision 1.3Dec 20, 2023Group: 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_atom_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_atom_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 1.4Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification
Remark 700 SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN ... SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN THE SHEET RECORDS BELOW, TWO SHEETS ARE DEFINED.

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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)46,4906
Polymers45,8221
Non-polymers6685
Water7,242402
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)47.540, 76.390, 104.340
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 / BACE1 / ASPARTYL PROTEASE 2 / ASP2 / ASP 2 / BETA-SITE AMYLOID PRECURSOR PROTEIN CLEAVING ENZYME 1 ...BACE1 / 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: 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.: 3 / 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-7F3 / (1S)-4-fluoro-1-(4-fluoro-3-pyrimidin-5-ylphenyl)-1-[2-(trifluoromethyl)pyridin-4-yl]-1H-isoindol-3-amine


Mass: 467.393 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H14F5N5
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 402 / 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 %
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: RIGAKU HTC / Detector: IMAGE PLATE / Date: Aug 20, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.79→35.87 Å / Num. obs: 36601 / % possible obs: 99.9 % / Observed criterion σ(I): 0 / Redundancy: 3.4 % / Biso Wilson estimate: 22.03 Å2 / Rmerge(I) obs: 0.04 / Net I/σ(I): 20.6
Reflection shellResolution: 1.79→1.84 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.26 / Mean I/σ(I) obs: 4.5 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.1refinement
MOSFLMdata reduction
SCALAdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PREVIOUSLY DETERMINED BACE1 STRUCTURE BASED ON PDB ENTRY 1FKN

1fkn


Resolution: 1.79→35.87 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.9379 / SU R Cruickshank DPI: 0.122 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.132 / SU Rfree Blow DPI: 0.12 / SU Rfree Cruickshank DPI: 0.115
Details: NUMBER OF LIBRARIES USED : 8. REFINEMENT NOTE: 1 IDEAL-DIST CONTACT TERM CONTACT SETUP. RESIDUE TYPES WITHOUT CCP4 ATOM TYPE IN LIBRARY=NA. NUMBER OF ATOMS WITH PROPER CCP4 ATOM TYPE=3431. ...Details: NUMBER OF LIBRARIES USED : 8. REFINEMENT NOTE: 1 IDEAL-DIST CONTACT TERM CONTACT SETUP. RESIDUE TYPES WITHOUT CCP4 ATOM TYPE IN LIBRARY=NA. NUMBER OF ATOMS WITH PROPER CCP4 ATOM TYPE=3431. NUMBER WITH APPROX DEFAULT CCP4 ATOM TYPE=0. NUMBER TREATED BY BAD NON-BONDED CONTACT CONTACTS=1.
RfactorNum. reflection% reflectionSelection details
Rfree0.2105 1824 4.99 %RANDOM
Rwork0.1756 ---
obs0.1775 36544 99.89 %-
Displacement parametersBiso mean: 25.06 Å2
Baniso -1Baniso -2Baniso -3
1--5.5769 Å20 Å20 Å2
2--0.6288 Å20 Å2
3---4.9482 Å2
Refine analyzeLuzzati coordinate error obs: 0.189 Å
Refinement stepCycle: LAST / Resolution: 1.79→35.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2951 0 47 402 3400
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.013114HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.124247HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1040SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes77HARMONIC2
X-RAY DIFFRACTIONt_gen_planes459HARMONIC5
X-RAY DIFFRACTIONt_it3114HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion4.16
X-RAY DIFFRACTIONt_other_torsion15.63
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion395SEMIHARMONIC5
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_contact3904SEMIHARMONIC4
LS refinement shellResolution: 1.79→1.84 Å / Total num. of bins used: 18
RfactorNum. reflection% reflection
Rfree0.314 143 4.84 %
Rwork0.2643 2814 -
all0.2667 2957 -
obs--99.89 %

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