2OAH

Crystal Structure of Human Beta Secretase Complexed with inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.217 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind beta-secretase in a N-terminal 10s-loop down conformation.

Stauffer, S.R.Stanton, M.G.Gregro, A.R.Steinbeiser, M.A.Shaffer, J.R.Nantermet, P.G.Barrow, J.C.Rittle, K.E.Collusi, D.Espeseth, A.S.Lai, M.T.Pietrak, B.L.Holloway, M.K.McGaughey, G.B.Munshi, S.K.Hochman, J.H.Simon, A.J.Selnick, H.G.Graham, S.L.Vacca, J.P.

(2007) Bioorg Med Chem Lett 17: 1788-1792

  • DOI: https://doi.org/10.1016/j.bmcl.2006.12.051
  • Primary Citation of Related Structures:  
    2OAH

  • PubMed Abstract: 

    A series of low-molecular weight 2,6-diamino-isonicotinamide BACE-1 inhibitors containing an amine transition-state isostere were synthesized and shown to be highly potent in both enzymatic and cell-based assays. These inhibitors contain a trans-S,S-methyl cyclopropane P(3) which bind BACE-1 in a 10s-loop down conformation giving rise to highly potent compounds with favorable molecular weight and moderate to high susceptibility to P-glycoprotein (P-gp) efflux.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. shaun_stauffer@merck.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1405Homo sapiensMutation(s): 2 
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
QIN
Query on QIN

Download Ideal Coordinates CCD File 
B [auth A]N-[(1S,2S)-2-AMINO-1-(3-THIENYLMETHYL)HEXYL]-2-({[(1S,2S)-2-METHYLCYCLOPROPYL]METHYL}AMINO)-6-[METHYL(METHYLSULFONYL)AMINO]ISONICOTINAMIDE
C24 H37 N5 O3 S2
MSSOOXCWRUWADA-CZGNIMDHSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
QIN PDBBind:  2OAH IC50: 11 (nM) from 1 assay(s)
BindingDB:  2OAH IC50: 11 (nM) from 1 assay(s)
Binding MOAD:  2OAH IC50: 11 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.217 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 104.755α = 90
b = 126.986β = 90
c = 76.411γ = 90
Software Package:
Software NamePurpose
CNXrefinement
CrystalCleardata collection
d*TREKdata reduction
d*TREKdata scaling
CNXphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

  • Released Date: 2007-08-14 
  • Deposition Author(s): Munshi, S.

Revision History  (Full details and data files)

  • Version 1.0: 2007-08-14
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2021-10-20
    Changes: Database references, Derived calculations
  • Version 1.3: 2023-08-30
    Changes: Data collection, Refinement description