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| | ==Crystal structure of BACE1 in complex with aminooxazoline xanthene 11a== | | ==Crystal structure of BACE1 in complex with aminooxazoline xanthene 11a== |
| - | <StructureSection load='4frk' size='340' side='right' caption='[[4frk]], [[Resolution|resolution]] 2.10Å' scene=''> | + | <StructureSection load='4frk' size='340' side='right'caption='[[4frk]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4frk]] 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=4FRK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4FRK FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4frk]] 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=4FRK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4FRK FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DWD:(4S)-2-(2-METHYLPROPOXY)-7-(PYRIMIDIN-5-YL)SPIRO[1,3-OXAZOLE-4,9-XANTHEN]-2-AMINE'>DWD</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DWD:(4S)-2-(2-METHYLPROPOXY)-7-(PYRIMIDIN-5-YL)SPIRO[1,3-OXAZOLE-4,9-XANTHEN]-2-AMINE'>DWD</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4fri|4fri]], [[4frj|4frj]]</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=4frk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4frk OCA], [https://pdbe.org/4frk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4frk RCSB], [https://www.ebi.ac.uk/pdbsum/4frk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4frk ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE, BACE1, KIAA1149 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4frk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4frk OCA], [http://pdbe.org/4frk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4frk RCSB], [http://www.ebi.ac.uk/pdbsum/4frk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4frk 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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| | ==See Also== | | ==See Also== |
| - | *[[Beta secretase|Beta secretase]] | + | *[[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: Long, A M]] | + | [[Category: Long AM]] |
| - | [[Category: Whittington, D A]] | + | [[Category: Whittington DA]] |
| - | [[Category: Alzheimer's disease]]
| + | |
| - | [[Category: Aspartic protease]]
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| - | [[Category: Hydrolase-inhibitor complex]]
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| - | [[Category: Membrane protein]]
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| 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
A structure- and property-based drug design approach was employed to identify aminooxazoline xanthenes as potent and selective human beta-secretase inhibitors. These compounds exhibited good enzyme, cell potency, and selectivity against the structurally related aspartyl protease cathepsin D. Our efforts resulted in the identification of a potent, orally bioavailable CNS penetrant compound that exhibited in vivo efficacy. A single oral dose of compound 11a resulted in a robust reduction of CNS Abeta40 in naive rats.
Structure and Property Based Design of Aminooxazoline Xanthenes as Selective and Orally Efficacious, CNS Penetrable BACE Inhibitors for the Treatment of Alzheimer's Disease.,Huang H, La DS, Cheng AC, Whittington DA, Patel VF, Chen K, Dineen TA, Epstein O, Graceffa R, Hickman D, Kiang YH, Louie S, Luo Y, Wahl R, Wen P, Wood S, Fremeau B J Med Chem. 2012 Aug 28. PMID:22928914[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
- ↑ Huang H, La DS, Cheng AC, Whittington DA, Patel VF, Chen K, Dineen TA, Epstein O, Graceffa R, Hickman D, Kiang YH, Louie S, Luo Y, Wahl R, Wen P, Wood S, Fremeau B. Structure and Property Based Design of Aminooxazoline Xanthenes as Selective and Orally Efficacious, CNS Penetrable BACE Inhibitors for the Treatment of Alzheimer's Disease. J Med Chem. 2012 Aug 28. PMID:22928914 doi:http://dx.doi.org/10.1021/jm300598e
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