› 4h3j

X-ray diffraction
1.6Å resolution

Structure of BACE Bound to 2-fluoro-5-(5-(2-imino-3-methyl-4-oxo-6-phenyloctahydro-1H-pyrrolo[3,4-d]pyrimidin-7a-yl)thiophen-2-yl)benzonitrile

Released:
DOI: 10.2210/pdb4h3j/pdb
PDB entry 4h3j coloured by chain, front view.
PDB entry 4h3j coloured by chain, side view.
PDB entry 4h3j coloured by chain, top view.
Source organism: Homo sapiens
Primary publication:
Design and validation of bicyclic iminopyrimidinones as beta amyloid cleaving enzyme-1 (BACE1) inhibitors: conformational constraint to favor a bioactive conformation.
Mandal M, Zhu Z, Cumming JN, Liu X, Strickland C, Mazzola RD, Caldwell JP, Leach P, Grzelak M, Hyde L, Zhang Q, Terracina G, Zhang L, Chen X, Kuvelkar R, Kennedy ME, Favreau L, Cox K, Orth P, Buevich A, Voigt J, Wang H, Kazakevich I, McKittrick BA, Greenlee W, Parker EM, Stamford AW
J Med Chem 55 9331-45 (2012)
PMID: 22989333

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
Molecule details ›
Chains: A, B
Length: 414 amino acids
Theoretical weight: 46.25 KDa
Source organism: Homo sapiens
Expression system: Escherichia coli BL21(DE3)
UniProt:
  • Canonical: P56817 (Residues: 41-454; Coverage: 86%)
Gene names: BACE, BACE1, KIAA1149
Sequence domains: Eukaryotic aspartyl protease
Structure domains: Acid Proteases

Ligands and Environments

2 bound ligands:
Ligand TLA 3 x TLA
Ligand 10W 2 x 10W
No modified residues

Experiments and Validation Details

Entry percentile scores
X-ray source: APS BEAMLINE 17-ID
Spacegroup: P212121
Unit cell:
a: 86.568Å b: 89.462Å c: 131.091Å
α: 90° β: 90° γ: 90°
R-values:
R R work R free
0.183 0.183 0.21
Expression system: Escherichia coli BL21(DE3)

Quick links

Citations

9 review citations

The evolution of amidine-based brain penetrant BACE1 inhibitors.
Oehlrich et al. (2014)
8 more