4K9H

Bace-1 inhibitor complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.29 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.202 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Hydroxyethylamine-based inhibitors of BACE1: P1-P3 macrocyclization can improve potency, selectivity, and cell activity.

Pennington, L.D.Whittington, D.A.Bartberger, M.D.Jordan, S.R.Monenschein, H.Nguyen, T.T.Yang, B.H.Xue, Q.M.Vounatsos, F.Wahl, R.C.Chen, K.Wood, S.Citron, M.Patel, V.F.Hitchcock, S.A.Zhong, W.

(2013) Bioorg Med Chem Lett 23: 4459-4464

  • DOI: https://doi.org/10.1016/j.bmcl.2013.05.028
  • Primary Citation of Related Structures:  
    4K8S, 4K9H, 4KE0, 4KE1

  • PubMed Abstract: 

    We describe a systematic study of how macrocyclization in the P₁-P₃ region of hydroxyethylamine-based inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme (BACE1) modulates in vitro activity. This study reveals that in a number of instances macrocyclization of bis-terminal dienes leads to improved potency toward BACE1 and selectivity against cathepsin D (CatD), as well as greater amyloid β-peptide (Aβ)-lowering activity in HEK293T cells stably expressing APPSW. However, for several closely related analogs the benefits of macrocyclization are attenuated by the effects of other structural features in different regions of the molecules. X-ray crystal structures of three of these novel macrocyclic inhibitors bound to BACE1 revealed their binding conformations and interactions with the enzyme.


  • Organizational Affiliation

    Medicinal Chemistry, Amgen, One Amgen Center Drive, Thousand Oaks, CA 91320, USA. lewpenn@icloud.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1
A, B, C
388Homo sapiensMutation(s): 0 
Gene Names: BACE1BACEKIAA1149
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
1QU
Query on 1QU

Download Ideal Coordinates CCD File 
D [auth A],
E [auth B],
F [auth C]
1-cyclopentyl-N-[(2S,3R)-3-hydroxy-1-phenyl-4-{[3-(trifluoromethyl)benzyl]amino}butan-2-yl]-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide
C33 H37 F3 N4 O4
QKLJNYJRYSKKKP-LMSSTIIKSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1QU Binding MOAD:  4K9H IC50: 76 (nM) from 1 assay(s)
PDBBind:  4K9H IC50: 76 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.29 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.202 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 82.538α = 90
b = 103.304β = 104.01
c = 100.856γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
X-PLORmodel building
REFMACrefinement
DENZOdata reduction
SCALEPACKdata scaling
X-PLORphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2013-07-10 
  • Deposition Author(s): Jordan, S.R.

Revision History  (Full details and data files)

  • Version 1.0: 2013-07-10
    Type: Initial release
  • Version 1.1: 2013-07-17
    Changes: Database references