Prediction of the tertiary structure of the beta-secretase zymogen

Biochemical and Biophysical Research Communications
Kuo-Chen Chou, W Jeffrey Howe

Abstract

beta-Secretase, also known as BACE, is a transmembrane aspartyl protease, which generates the N terminus of Alzheimer's disease amyloid beta-peptide. The activity of beta-secretase is the rate-limiting step of brain plaques production in vivo, and hence is a potential target for disease modifying drugs for Alzheimer's disease. To better understand the mechanism of action of beta-secretase and help explore novel strategies for drug discovery for Alzheimer's disease, it is important to elucidate the three-dimensional structure of its zymogen. Based on the X-ray structure of the enzyme's protease domain and the X-ray structure of pepsinogen, a model of the three-dimensional structure of the beta-secretase zymogen has been constructed. Comparison of the computed structure of pro-BACE with X-ray structures of pepsinogen and progastricsin (two other pro-aspartyl proteases) reveals a significant difference in the relationship of the pro-segment to the catalytic aspartates. In both pepsinogen and progastricsin a lysine side-chain in the pro-segment forms a salt bridge to the two catalytic aspartates, occupying the position normally occupied by a catalytic water. In the pro-BACE model there is no salt bridge, and the corresponding resid...Continue Reading

Citations

Apr 7, 2012·Current Gerontology and Geriatrics Research·Robin L Webb, M Paul Murphy
Mar 22, 2014·International Journal of Molecular Sciences·Yue-Nong FanKuo-Chen Chou
Aug 1, 2007·Expert Opinion on Drug Discovery·Georgia B McGaughey, M Katharine Holloway
Apr 23, 2005·Biochemical and Biophysical Research Communications·Kuo-Chen Chou
Mar 23, 2004·Biochemical and Biophysical Research Communications·Kuo-Chen Chou
Jun 5, 2004·Journal of Theoretical Biology·Yu-dong CaiKuo-Chen Chou
Jun 10, 2006·Journal of Theoretical Biology·R VarónB H Havsteen
Jan 14, 2010·Journal of Neurochemistry·David W KlaverDavid H Small
Oct 28, 2019·Current Topics in Medicinal Chemistry·Kuo-Chen Chou
Nov 30, 2019·Current Pharmaceutical Design·Kuo-Chen Chou
Oct 30, 2019·Applied Biochemistry and Biotechnology·Mandana BehbahaniHassan Mohabatkar
Jul 3, 2019·Frontiers in Bioengineering and Biotechnology·Abdul RazzaqMuhammad Ashraf
Dec 6, 2019·Database : the Journal of Biological Databases and Curation·Lei ZhengYongchun Zuo
Apr 6, 2019·Current Medicinal Chemistry·Qingjun PanHua-Feng Liu
Mar 23, 2011·Journal of Theoretical Biology·Jiapu ZhangChangzhi Wu
Aug 2, 2003·Biochemical and Biophysical Research Communications·Kuo-Chen ChouWei-Zhu Zhong
Feb 1, 2005·Computational Biology and Chemistry·Suzanne SiroisKuo-Chen Chou
Dec 6, 2005·Biochemical and Biophysical Research Communications·Kuo-Chen Chou, Yu-Dong Cai
May 2, 2006·Biochemical and Biophysical Research Communications·Dong-Qing WeiKuo-Chen Chou
Nov 15, 2008·Analytical Biochemistry·Hong-Bin Shen, Kuo-Chen Chou
May 25, 2004·Journal of Chemical Information and Computer Sciences·Suzanne SiroisKuo-Chen Chou
Aug 12, 2009·Biochemical and Biophysical Research Communications·Jing-Fang WangKuo-Chen Chou

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