3R2F

Crystal structure of beta-site app-cleaving enzyme 1 (BACE-WT) complex with BMS-693391 AKA (2S)-2-((3R)-3-acetamido-3-isobutyl-2-oxo-1-pyrrolidinyl)-N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-2-((2R,4R)-4-propoxy-2-pyrrolidinyl)ethyl)-4-phenylbutanamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.53 Å
  • R-Value Free: 0.330 
  • R-Value Work: 0.280 
  • R-Value Observed: 0.283 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Monosubstituted {gamma}-lactam and conformationally constrained 1,3-diaminopropan-2-ol transition-state isostere inhibitors of {beta}-secretase (BACE).

Boy, K.M.Guernon, J.M.Shi, J.Toyn, J.H.Meredith, J.E.Barten, D.M.Burton, C.R.Albright, C.F.Marcinkeviciene, J.Good, A.C.Tebben, A.J.Muckelbauer, J.K.Camac, D.M.Lentz, K.A.Bronson, J.J.Olson, R.E.Macor, J.E.Thompson, L.A.

(2011) Bioorg Med Chem Lett 21: 6916-6924

  • DOI: https://doi.org/10.1016/j.bmcl.2011.06.109
  • Primary Citation of Related Structures:  
    3R2F

  • PubMed Abstract: 

    The synthesis, evaluation, and structure-activity relationships of a class of γ-lactam 1,3-diaminopropan-2-ol transition-state isostere inhibitors of BACE are discussed. Two strategies for optimizing lead compound 1a are presented. Reducing the overall size of the inhibitors resulted in the identification of γ-lactam 1i, whereas the introduction of conformational constraint on the prime-side of the inhibitor generated compounds such as the 3-hydroxypyrrolidine inhibitor 28n. The full in vivo profile of 1i in rats and 28n in Tg 2576 mice is presented.


  • Organizational Affiliation

    Department of Neuroscience Discovery Chemistry, Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, USA. boyk@bms.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1A,
B,
C [auth D],
D [auth E]
455Homo sapiensMutation(s): 0 
Gene Names: BACEBACE1KIAA1149
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
PB0
Query on PB0

Download Ideal Coordinates CCD File 
E [auth A],
F [auth B],
G [auth D],
H [auth E]
(2S)-2-[(3R)-3-(acetylamino)-3-(2-methylpropyl)-2-oxopyrrolidin-1-yl]-N-{(1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-[(2R,4R)-4-propoxypyrrolidin-2-yl]propan-2-yl}-4-phenylbutanamide
C36 H50 F2 N4 O5
LPZOLMFQGUDKQH-ZXWXCOCLSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
PB0 PDBBind:  3R2F IC50: 1.4 (nM) from 1 assay(s)
BindingDB:  3R2F IC50: min: 1.4, max: 2 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.53 Å
  • R-Value Free: 0.330 
  • R-Value Work: 0.280 
  • R-Value Observed: 0.283 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 86.306α = 90
b = 130.255β = 96.53
c = 86.927γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
CNSrefinement
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
CNSphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-08-31
    Type: Initial release
  • Version 1.1: 2013-06-19
    Changes: Database references
  • Version 1.2: 2019-07-17
    Changes: Data collection, Refinement description