2F3F

Crystal Structure of the Bace complex with BDF488, a macrocyclic inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.192 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structure-based design and synthesis of macroheterocyclic peptidomimetic inhibitors of the aspartic protease beta-site amyloid precursor protein cleaving enzyme (BACE).

Hanessian, S.Yang, G.Rondeau, J.-M.Neumann, U.Betschart, C.Tintelnot-Blomley, M.

(2006) J Med Chem 49: 4544-4567

  • DOI: https://doi.org/10.1021/jm060154a
  • Primary Citation of Related Structures:  
    2F3E, 2F3F

  • PubMed Abstract: 

    Based on the X-ray cocrystal structure of the Tang-Ghosh heptapeptide inhibitor 1 (OM00-3), a series of macroheterocyclic analogues were designed and synthesized. Analogues containing dithia, dioxa, oxathia, and carbathia macrocycles were synthesized by methods relying on ring-closing olefin metathesis for the dioxa analogues and by alkylation of thiolates or bisthiolates for the others. Molecular modeling suggested that the incorporation of piperidine units appended to the macrocycles improved interactions through additional H-bonds and introduced further rigidity. These were synthesized in enantiomerically pure form using enzyme-catalyzed desymmetrization and diastereomer separation. Inhibitory activity on beta-site amyloid precursor protein cleaving enzyme (BACE) was observed with several macroheterocyclic inhibitors and structure-activity relationship (SAR) correlations were deduced. Cocrystal structures of two synthetic analogues revealed interesting and unexpected binding interactions.


  • Organizational Affiliation

    Department of Chemistry, Université de Montréal, C. P. 6128, Station Centre-ville, Montréal, Quebec H3C 3J7, Canada. stephen.hanessian@umontreal.ca


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1
A, B, C
402Homo sapiensMutation(s): 0 
Gene Names: BACE1BACE
EC: 3.4.23.46
UniProt & NIH Common Fund Data Resources
Find proteins for P56817 (Homo sapiens)
Explore P56817 
Go to UniProtKB:  P56817
PHAROS:  P56817
GTEx:  ENSG00000186318 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP56817
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
AXF
Query on AXF

Download Ideal Coordinates CCD File 
D [auth A],
E [auth B],
F [auth C]
(2R,4S)-N-BUTYL-4-HYDROXY-2-METHYL- 4-((E)-(4AS,12R,15S,17AS)-15-METHYL -14,17-DIOXO-2,3,4,4A,6,9,11,12,13, 14,15,16,17,17A-TETRADECAHYDRO-1H-5 ,10-DITHIA-1,13,16-TRIAZA-BENZOCYCL OPENTADECEN-12-YL)-BUTYRAMIDE
C24 H42 N4 O4 S2
FIWCVIADXWJIGF-NFXSCPKSSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
AXF BindingDB:  2F3F IC50: 190 (nM) from 1 assay(s)
PDBBind:  2F3F IC50: 190 (nM) from 1 assay(s)
Binding MOAD:  2F3F IC50: 190 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.192 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 82.25α = 90
b = 103.202β = 103.03
c = 100.997γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACTdata extraction
CNXphasing
CNXrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2006-09-05
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2017-10-18
    Changes: Refinement description