› 4k8s

X-ray diffraction
2.39Å resolution

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

Released:
DOI: 10.2210/pdb4k8s/pdb
PDB entry 4k8s coloured by chain, front view.
PDB entry 4k8s coloured by chain, side view.
PDB entry 4k8s coloured by chain, top view.
Source organism: Homo sapiens
Primary publication:
Hydroxyethylamine-based inhibitors of BACE1: P₁-P₃ macrocyclization can improve potency, selectivity, and cell activity.
Pennington LD, Whittington DA, Bartberger MD, Jordan SR, Monenschein H, Nguyen TT, Yang BH, Xue QM, Vounatsos F, Wahl RC, Chen K, Wood S, Citron M, Patel VF, Hitchcock SA, Zhong W
Bioorg Med Chem Lett 23 4459-64 (2013)
PMID: 23769639

Function and Biology Details

Reaction catalysed: 
Broad endopeptidase specificity. Cleaves Glu-Val-Asn-Leu-|-Asp-Ala-Glu-Phe in the Swedish variant of Alzheimer's amyloid precursor protein.
Biochemical function:
Biological process:
Cellular component:
Sequence domains:

Structure analysis Details

Assembly composition:
monomeric (preferred)
Assembly name:
PDBe Complex ID:
PDB-CPX-157541 (preferred)
Entry contents:
1 distinct polypeptide molecule
Macromolecule:
Beta-secretase 1 Chains: A, B, C
Molecule details ›
Chains: A, B, C
Length: 388 amino acids
Theoretical weight: 43.26 KDa
Source organism: Homo sapiens
Expression system: Escherichia coli
UniProt:
  • Canonical: P56817 (Residues: 59-446; Coverage: 81%)
Gene names: BACE, BACE1, KIAA1149
Sequence domains: Eukaryotic aspartyl protease
Structure domains: Acid Proteases

Ligands and Environments

1 bound ligand:
Ligand 1QT 3 x 1QT
No modified residues

Experiments and Validation Details

Entry percentile scores
X-ray source: RIGAKU FR-E DW
Spacegroup: P21
Unit cell:
a: 81.841Å b: 102.563Å c: 101.318Å
α: 90° β: 105.24° γ: 90°
R-values:
R R work R free
0.212 0.21 0.26
Expression system: Escherichia coli

Quick links

Citations

2 review citations

BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease.
Ghosh et al. (2014)
1 more

3 mentions without citation

Comparison of affinity ranking using AutoDock-GPU and MM-GBSA scores for BACE-1 inhibitors in the D3R Grand Challenge 4.
El Khoury et al. (2019)
2 more