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| | <StructureSection load='5tol' size='340' side='right'caption='[[5tol]], [[Resolution|resolution]] 2.51Å' scene=''> | | <StructureSection load='5tol' size='340' side='right'caption='[[5tol]], [[Resolution|resolution]] 2.51Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5tol]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TOL OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5TOL FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5tol]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TOL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TOL FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7H3:N-{3-[(4AR,7AR)-2-AMINO-4,4A,5,6-TETRAHYDRO-7AH-FURO[2,3-D][1,3]THIAZIN-7A-YL]-4-FLUOROPHENYL}-5-BROMOPYRIDINE-2-CARBOXAMIDE'>7H3</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.51Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE1, BACE, KIAA1149 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7H3:N-{3-[(4AR,7AR)-2-AMINO-4,4A,5,6-TETRAHYDRO-7AH-FURO[2,3-D][1,3]THIAZIN-7A-YL]-4-FLUOROPHENYL}-5-BROMOPYRIDINE-2-CARBOXAMIDE'>7H3</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] </span></td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5tol FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tol OCA], [https://pdbe.org/5tol PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tol RCSB], [https://www.ebi.ac.uk/pdbsum/5tol PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tol ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5tol FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tol OCA], [http://pdbe.org/5tol PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tol RCSB], [http://www.ebi.ac.uk/pdbsum/5tol PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tol ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/BACE1_HUMAN 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.<ref>PMID:10677483</ref> <ref>PMID:20354142</ref> | + | [https://www.uniprot.org/uniprot/BACE1_HUMAN 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.<ref>PMID:10677483</ref> <ref>PMID:20354142</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Memapsin 2]]
| + | [[Category: Muckelbauer JK]] |
| - | [[Category: Muckelbauer, J K]] | + | |
| - | [[Category: Asp2]]
| + | |
| - | [[Category: Aspartyl protease]]
| + | |
| - | [[Category: Bace]]
| + | |
| - | [[Category: Bace1]]
| + | |
| - | [[Category: Flj90568]]
| + | |
| - | [[Category: Hspc104]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Kiaa1149]]
| + | |
| 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]
Publication Abstract from PubMed
This Letter describes the synthesis and structure-activity relationships of a series of furo[2,3-d][1,3]thiazinamine BACE1 inhibitors. The co-crystal structure of a representative thiazinamine 2e bound with the BACE1 active site displayed a binding mode driven by interactions with the catalytic aspartate dyad and engagement of the biaryl amide toward the S1 and S3 pockets. This work indicates that furo[2,3-d]thiazine can serve as a viable bioisostere of the known furo[3,4-d]thiazine.
Discovery of furo[2,3-d][1,3]thiazinamines as beta amyloid cleaving enzyme-1 (BACE1) inhibitors.,Wu YJ, Guernon J, Rajamani R, Toyn JH, Ahlijanian MK, Albright CF, Muckelbauer J, Chang C, Camac D, Macor JE, Thompson LA Bioorg Med Chem Lett. 2016 Dec 1;26(23):5729-5731. doi:, 10.1016/j.bmcl.2016.10.055. Epub 2016 Oct 20. PMID:27816517[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Wu YJ, Guernon J, Rajamani R, Toyn JH, Ahlijanian MK, Albright CF, Muckelbauer J, Chang C, Camac D, Macor JE, Thompson LA. Discovery of furo[2,3-d][1,3]thiazinamines as beta amyloid cleaving enzyme-1 (BACE1) inhibitors. Bioorg Med Chem Lett. 2016 Dec 1;26(23):5729-5731. doi:, 10.1016/j.bmcl.2016.10.055. Epub 2016 Oct 20. PMID:27816517 doi:http://dx.doi.org/10.1016/j.bmcl.2016.10.055
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