| Structural highlights
4i12 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , |
| Related: | 4hzi, 4i0z, 4i0e, 4i0d, 4i0f, 4i0g, 4i10, 4i1c |
| Gene: | BACE1, BACE, KIAA1149 (HUMAN) |
| Activity: | Memapsin 2, with EC number 3.4.23.46 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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]
Publication Abstract from PubMed
Utilizing a structure based design approach, combined with extensive medicinal chemistry execution, highly selective, potent and novel BACE1 inhibitor 8 (BACE1 Alpha assay IC50=8nM) was made from a weak muM potency hit in an extremely efficient way. The detailed SAR and general design approaches will be discussed.
Design and synthesis of thiophene dihydroisoquinolines as novel BACE1 inhibitors.,Xu YZ, Yuan S, Bowers S, Hom RK, Chan W, Sham HL, Zhu YL, Beroza P, Pan H, Brecht E, Yao N, Lougheed J, Yan J, Tam D, Ren Z, Ruslim L, Bova MP, Artis DR Bioorg Med Chem Lett. 2013 May 15;23(10):3075-80. doi:, 10.1016/j.bmcl.2013.03.009. Epub 2013 Mar 21. PMID:23570791[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
- ↑ Xu YZ, Yuan S, Bowers S, Hom RK, Chan W, Sham HL, Zhu YL, Beroza P, Pan H, Brecht E, Yao N, Lougheed J, Yan J, Tam D, Ren Z, Ruslim L, Bova MP, Artis DR. Design and synthesis of thiophene dihydroisoquinolines as novel BACE1 inhibitors. Bioorg Med Chem Lett. 2013 May 15;23(10):3075-80. doi:, 10.1016/j.bmcl.2013.03.009. Epub 2013 Mar 21. PMID:23570791 doi:10.1016/j.bmcl.2013.03.009
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