HUMAN BACE-1 IN COMPLEX WITH 6-(ETHYLAMINO)-N-((1S,2R)-2-HYDROXY-3-(((3-(METHYLOXY)PHENYL)METHYL)AMINO)-1-(PHENYLMETHYL)PROPYL)-1-METHYL-1,3,4,5-TETRAHYDRO-2,1-BENZOTHIAZEPINE-8-CARBOXAMIDE 2,2-DIOXIDE
2wf3 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.
[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
Our first generation of hydroxyethylamine transition-state mimetic BACE-1 inhibitors allowed us to validate BACE-1 as a key target for Alzheimer's disease by demonstrating amyloid lowering in an animal model, albeit at rather high doses. Finding a molecule from this series which was active at lower oral doses proved elusive and demonstrated the need to find a novel series of inhibitors with improved pharmacokinetics. This Letter describes the discovery of such inhibitors.
Second generation of BACE-1 inhibitors part 2: Optimisation of the non-prime side substituent.,Charrier N, Clarke B, Demont E, Dingwall C, Dunsdon R, Hawkins J, Hubbard J, Hussain I, Maile G, Matico R, Mosley J, Naylor A, O'Brien A, Redshaw S, Rowland P, Soleil V, Smith KJ, Sweitzer S, Theobald P, Vesey D, Walter DS, Wayne G Bioorg Med Chem Lett. 2009 Jul 1;19(13):3669-73. Epub 2009 Apr 5. PMID:19477642[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
↑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
↑Charrier N, Clarke B, Demont E, Dingwall C, Dunsdon R, Hawkins J, Hubbard J, Hussain I, Maile G, Matico R, Mosley J, Naylor A, O'Brien A, Redshaw S, Rowland P, Soleil V, Smith KJ, Sweitzer S, Theobald P, Vesey D, Walter DS, Wayne G. Second generation of BACE-1 inhibitors part 2: Optimisation of the non-prime side substituent. Bioorg Med Chem Lett. 2009 Jul 1;19(13):3669-73. Epub 2009 Apr 5. PMID:19477642 doi:10.1016/j.bmcl.2009.03.150
