3FKT

Crystal Structure of Human Beta Secretase Complexed with Spiropiperdine Iminohydantoin Inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.217 
  • R-Value Work: 0.182 
  • R-Value Observed: 0.183 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Discovery and X-ray Crystallographic Analysis of a Iminohydantoin Inhibitor of beta-Secretase

Barrow, J.C.Stauffer, S.R.Rittle, K.E.Ngo, P.L.Yang, M.S.Graham, S.McGaughey, G.Holloway, K.Tugusheva, S.K.Lai, M.Espeseth, A.S.Xu, M.Huang, Q.Zuck, P.Levorse, D.A.Hazuda, D.Vacca, J.P.

(2008) J Med Chem 51: 6259-6262

  • DOI: https://doi.org/10.1021/jm800914n
  • Primary Citation of Related Structures:  
    3FKT

  • PubMed Abstract: 

    A high-throughput screen at 100 microM inhibitor concentration for the BACE-1 enzyme revealed a novel spiropiperidine iminohydantoin aspartyl protease inhibitor template. An X-ray cocrystal structure with BACE-1 revealed a novel mode of binding whereby the inhibitor interacts with the catalytic aspartates via bridging water molecules. Using the crystal structure as a guide, potent compounds with good brain penetration were designed.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. james_barrow@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: 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
SII
Query on SII

Download Ideal Coordinates CCD File 
B [auth A]N-(4-{[4-(cyclohexylamino)-1-(3-fluorophenyl)-2-oxo-1,3,8-triazaspiro[4.5]dec-3-en-8-yl]methyl}phenyl)acetamide
C28 H34 F N5 O2
VXIOVOURIXSOTD-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
SII BindingDB:  3FKT IC50: 2800 (nM) from 1 assay(s)
PDBBind:  3FKT IC50: 2800 (nM) from 1 assay(s)
Binding MOAD:  3FKT IC50: 2800 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.217 
  • R-Value Work: 0.182 
  • R-Value Observed: 0.183 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 103.743α = 90
b = 128.042β = 90
c = 76.768γ = 90
Software Package:
Software NamePurpose
CCP4model building
REFMACrefinement
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
CCP4phasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

  • Released Date: 2009-01-20 
  • Deposition Author(s): Munshi, S.
  • This entry supersedes: 3E3W

Revision History  (Full details and data files)

  • Version 1.0: 2009-01-20
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2018-04-04
    Changes: Data collection
  • Version 1.3: 2021-10-20
    Changes: Database references, Derived calculations
  • Version 1.4: 2023-09-06
    Changes: Data collection, Refinement description