2IRZ

Crystal structure of human Beta-secretase complexed with inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.219 
  • R-Value Observed: 0.219 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Discovery of oxadiazoyl tertiary carbinamine inhibitors of beta-secretase (BACE-1).

Rajapakse, H.A.Nantermet, P.G.Selnick, H.G.Munshi, S.McGaughey, G.B.Lindsley, S.R.Young, M.B.Lai, M.T.Espeseth, A.S.Shi, X.P.Colussi, D.Pietrak, B.Crouthamel, M.C.Tugusheva, K.Huang, Q.Xu, M.Simon, A.J.Kuo, L.Hazuda, D.J.Graham, S.Vacca, J.P.

(2006) J Med Chem 49: 7270-7273

  • DOI: https://doi.org/10.1021/jm061046r
  • Primary Citation of Related Structures:  
    2IRZ, 2IS0

  • PubMed Abstract: 

    We describe the discovery and optimization of tertiary carbinamine derived inhibitors of the enzyme beta-secretase (BACE-1). These novel non-transition-state-derived ligands incorporate a single primary amine to interact with the catalytic aspartates of the target enzyme. Optimization of this series provided inhibitors with intrinsic and functional potency comparable to evolved transition state isostere derived inhibitors of BACE-1.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, West Point, Pennsylvania 19486, USA. hemaka_rajapakse@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
I02
Query on I02

Download Ideal Coordinates CCD File 
B [auth A]3-{5-[(1R)-1-AMINO-1-METHYL-2-PHENYLETHYL]-1,3,4-OXADIAZOL-2-YL}-N-[(1R)-1-(4-FLUOROPHENYL)ETHYL]-5-[METHYL(METHYLSULFONYL)AMINO]BENZAMIDE
C28 H30 F N5 O4 S
QEJSJQVKMSAHHX-KWMCUTETSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
I02 BindingDB:  2IRZ IC50: min: 9, max: 60 (nM) from 3 assay(s)
Binding MOAD:  2IRZ IC50: 12 (nM) from 1 assay(s)
PDBBind:  2IRZ IC50: 12 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.219 
  • R-Value Observed: 0.219 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 104.53α = 90
b = 127.78β = 90
c = 76.47γ = 90
Software Package:
Software NamePurpose
CNXrefinement
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
CNXphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

  • Released Date: 2006-11-14 
  • Deposition Author(s): Munshi, S.

Revision History  (Full details and data files)

  • Version 1.0: 2006-11-14
    Type: Initial release
  • Version 1.1: 2007-10-11
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2021-10-20
    Changes: Database references, Derived calculations
  • Version 1.4: 2023-08-30
    Changes: Data collection, Refinement description