Insights from modeling the tertiary structure of human BACE2.
BACE1, or beta-secretase, is a putative prime therapeutic target for the treatment of Alzheimer's disease. Mapping to the Down syndrome critical region (chromosome 21) and identified as a homologue of BACE1, BACE2 also cleaves amyloid precursor protein at the beta-site. Thus, BACE2, named also as Asp1 or Memapsin1, represents a second beta-secretase candidate. In this paper, the tertiary structure of the protease domain of BACE2 was developed. Although the overall structural topology between BACE1 and BACE2 protease domains is quite similar, the former contains 3 disulfide bonds but the latter only two. Particularly, a subtle structural difference around the DTG/DSG active site between the two structures has been observed that is useful for the in-depth selectivity study of BACE1 and BACE2 inhibitors, stimulating new therapeutic strategies for the treatment of Alzheimer's disease and Down syndrome as well.
Chou
Kuo-Chen
KC
Gordon Life Science Institute, San Diego, California 92130, USA. lifescience@san.rr.com
D000544:Alzheimer Disease / Q000188:drug therapy; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D020134:Catalytic Domain; D019295:Computational Biology; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D004220:Disulfides / Q000737:chemistry; D010450:Endopeptidases / Q000737:chemistry / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D040681:Structural Homology, Protein
D004220:Disulfides; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human