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- PDB-4b00: Design and Synthesis of BACE1 Inhibitors with In Vivo Brain Reduc... -

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Entry
Database: PDB / ID: 4b00
TitleDesign and Synthesis of BACE1 Inhibitors with In Vivo Brain Reduction of beta-Amyloid Peptides (COMPOUND (R)-41)
ComponentsBETA-SECRETASE 1
KeywordsHYDROLASE / AMINOISOINDOLE / ALZHEIMER'S DISEASE
Function / homology
Function and homology information


memapsin 2 / Golgi-associated vesicle lumen / beta-aspartyl-peptidase activity / signaling receptor ligand precursor processing / amyloid-beta formation / amyloid precursor protein catabolic process / membrane protein ectodomain proteolysis / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / prepulse inhibition ...memapsin 2 / Golgi-associated vesicle lumen / beta-aspartyl-peptidase activity / signaling receptor ligand precursor processing / amyloid-beta formation / amyloid precursor protein catabolic process / membrane protein ectodomain proteolysis / amyloid-beta metabolic process / detection of mechanical stimulus involved in sensory perception of pain / prepulse inhibition / cellular response to manganese ion / multivesicular body / presynaptic modulation of chemical synaptic transmission / protein serine/threonine kinase binding / cellular response to copper ion / hippocampal mossy fiber to CA3 synapse / trans-Golgi network / recycling endosome / protein processing / response to lead ion / cellular response to amyloid-beta / synaptic vesicle / late endosome / peptidase activity / positive regulation of neuron apoptotic process / amyloid-beta binding / endopeptidase activity / amyloid fibril formation / aspartic-type endopeptidase activity / early endosome / lysosome / endosome / endosome membrane / membrane raft / endoplasmic reticulum lumen / Amyloid fiber formation / axon / neuronal cell body / dendrite / enzyme binding / cell surface / Golgi apparatus / 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-I6X / Beta-secretase 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.83 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 / 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 1.3Apr 4, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.4Dec 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 / 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
Revision 1.5Nov 13, 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)46,5356
Polymers45,8221
Non-polymers7135
Water6,557364
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)47.956, 75.910, 104.646
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.: 4 / Source method: obtained synthetically / Formula: C2H3O2
#3: Chemical ChemComp-I6X / 5-{(1R)-3-amino-4-fluoro-1-[3-(5-prop-1-yn-1-ylpyridin-3-yl)phenyl]-1H-isoindol-1-yl}-1-ethyl-3-methylpyridin-2(1H)-one


Mass: 476.544 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H25FN4O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 364 / 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: 2.06 Å3/Da / Density % sol: 40 %
Description: RIGID BODY REFINEMENT USING REFMAC5 AND A PREVIOUSLY DETERMINED BACE1 STRUCTURE BASED ON THE PUBLISHED 1FKN STRUCTURE
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 SATURN A200 / Detector: CCD / Date: Oct 27, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.83→43.08 Å / Num. obs: 34330 / % possible obs: 99.6 % / Observed criterion σ(I): 0 / Redundancy: 3 % / Biso Wilson estimate: 23.05 Å2 / Rmerge(I) obs: 0.05 / Net I/σ(I): 15
Reflection shellResolution: 1.83→1.93 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.45 / Mean I/σ(I) obs: 2.1 / % possible all: 99.8

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Processing

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

1fkn


Resolution: 1.83→43.08 Å / Cor.coef. Fo:Fc: 0.9438 / Cor.coef. Fo:Fc free: 0.9086 / SU R Cruickshank DPI: 0.129 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.139 / SU Rfree Blow DPI: 0.135 / SU Rfree Cruickshank DPI: 0.13
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY.
RfactorNum. reflection% reflectionSelection details
Rfree0.2258 1711 5.01 %RANDOM
Rwork0.1731 ---
obs0.1756 34169 99.16 %-
Displacement parametersBiso mean: 26.56 Å2
Baniso -1Baniso -2Baniso -3
1--4.4965 Å20 Å20 Å2
2---2.4555 Å20 Å2
3---6.9521 Å2
Refine analyzeLuzzati coordinate error obs: 0.188 Å
Refinement stepCycle: LAST / Resolution: 1.83→43.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2949 0 52 364 3365
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.013109HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.144235HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1036SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes77HARMONIC2
X-RAY DIFFRACTIONt_gen_planes469HARMONIC5
X-RAY DIFFRACTIONt_it3109HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion4
X-RAY DIFFRACTIONt_other_torsion15.9
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_contact3824SEMIHARMONIC4
LS refinement shellResolution: 1.83→1.89 Å / Total num. of bins used: 17
RfactorNum. reflection% reflection
Rfree0.2773 145 4.98 %
Rwork0.2398 2764 -
all0.2417 2909 -
obs--99.16 %

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