| Structural highlights
Function
[BACE1_HUMAN] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.[1] [2]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
We have developed a novel series of heteroaromatic BACE-1 inhibitors. These inhibitors interact with the enzyme in a unique fashion that allows for potent binding in a non-traditional paradigm. In addition to the elucidation of their binding profile, we have discovered a pH dependent effect on the binding affinity as a result of the intrinsic pK(a) of these inhibitors and the pH of the BACE-1 enzyme binding assay.
Discovery of aminoheterocycles as a novel beta-secretase inhibitor class: pH dependence on binding activity part 1.,Stachel SJ, Coburn CA, Rush D, Jones KL, Zhu H, Rajapakse H, Graham SL, Simon A, Katharine Holloway M, Allison TJ, Munshi SK, Espeseth AS, Zuck P, Colussi D, Wolfe A, Pietrak BL, Lai MT, Vacca JP Bioorg Med Chem Lett. 2009 Jun 1;19(11):2977-80. Epub 2009 Apr 18. PMID:19409780[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1456-60. PMID:10677483
- ↑ Okada H, Zhang W, Peterhoff C, Hwang JC, Nixon RA, Ryu SH, Kim TW. Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing. FASEB J. 2010 Aug;24(8):2783-94. doi: 10.1096/fj.09-146357. Epub 2010 Mar 30. PMID:20354142 doi:10.1096/fj.09-146357
- ↑ Stachel SJ, Coburn CA, Rush D, Jones KL, Zhu H, Rajapakse H, Graham SL, Simon A, Katharine Holloway M, Allison TJ, Munshi SK, Espeseth AS, Zuck P, Colussi D, Wolfe A, Pietrak BL, Lai MT, Vacca JP. Discovery of aminoheterocycles as a novel beta-secretase inhibitor class: pH dependence on binding activity part 1. Bioorg Med Chem Lett. 2009 Jun 1;19(11):2977-80. Epub 2009 Apr 18. PMID:19409780 doi:10.1016/j.bmcl.2009.04.033
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