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| | ==Crystal Structure of Human BACE-1 in Complex with amino-1,4-oxazine compound 4== | | ==Crystal Structure of Human BACE-1 in Complex with amino-1,4-oxazine compound 4== |
| - | <StructureSection load='6fgy' size='340' side='right' caption='[[6fgy]], [[Resolution|resolution]] 1.54Å' scene=''> | + | <StructureSection load='6fgy' size='340' side='right'caption='[[6fgy]], [[Resolution|resolution]] 1.54Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6fgy]] 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=6FGY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FGY FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6fgy]] 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=6FGY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6FGY FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=D9W:~{N}-[3-[(3~{R})-5-azanyl-3-methyl-2,6-dihydro-1,4-oxazin-3-yl]phenyl]-5-bromanyl-pyridine-2-carboxamide'>D9W</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]] 1.54Å</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=D9W:~{N}-[3-[(3~{R})-5-azanyl-3-methyl-2,6-dihydro-1,4-oxazin-3-yl]phenyl]-5-bromanyl-pyridine-2-carboxamide'>D9W</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=6fgy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fgy OCA], [https://pdbe.org/6fgy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6fgy RCSB], [https://www.ebi.ac.uk/pdbsum/6fgy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6fgy ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6fgy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fgy OCA], [http://pdbe.org/6fgy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fgy RCSB], [http://www.ebi.ac.uk/pdbsum/6fgy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fgy 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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| | </div> | | </div> |
| | <div class="pdbe-citations 6fgy" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6fgy" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Beta secretase 3D structures|Beta secretase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Memapsin 2]] | + | [[Category: Large Structures]] |
| - | [[Category: Bourgier, E]] | + | [[Category: Bourgier E]] |
| - | [[Category: Rondeau, J M]] | + | [[Category: Rondeau J-M]] |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Oxazine]]
| + | |
| 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
New amino-1,4-oxazine derived BACE-1 inhibitors were explored and various synthetic routes developed. The binding mode of the inhibitors was elucidated by co-crystallization of 4 with BACE-1 and X-ray analysis. Subsequent optimization led to inhibitors with low double digit nanomolar activity in a biochemical and single digit nanomolar potency in a cellular assays. To assess the inhibitors for their permeation properties and potential to cross the blood-brain-barrier a MDR1-MDCK cell model was successfully applied. Compound 8a confirmed the in vitro results by dose-dependently reducing Abeta levels in mice in an acute treatment regimen.
Discovery of amino-1,4-oxazines as potent BACE-1 inhibitors.,Veenstra SJ, Rueeger H, Voegtle M, Lueoend R, Holzer P, Hurth K, Tintelnot-Blomley M, Frederiksen M, Rondeau JM, Jacobson L, Staufenbiel M, Neumann U, Machauer R Bioorg Med Chem Lett. 2018 May 3. pii: S0960-894X(18)30393-7. doi:, 10.1016/j.bmcl.2018.05.003. PMID:29764741[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
- ↑ Veenstra SJ, Rueeger H, Voegtle M, Lueoend R, Holzer P, Hurth K, Tintelnot-Blomley M, Frederiksen M, Rondeau JM, Jacobson L, Staufenbiel M, Neumann U, Machauer R. Discovery of amino-1,4-oxazines as potent BACE-1 inhibitors. Bioorg Med Chem Lett. 2018 May 3. pii: S0960-894X(18)30393-7. doi:, 10.1016/j.bmcl.2018.05.003. PMID:29764741 doi:http://dx.doi.org/10.1016/j.bmcl.2018.05.003
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