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| | ==Design and synthesis of potent hydroxyethylamine (hea) bace-1 inhibitors== | | ==Design and synthesis of potent hydroxyethylamine (hea) bace-1 inhibitors== |
| - | <StructureSection load='4exg' size='340' side='right' caption='[[4exg]], [[Resolution|resolution]] 1.80Å' scene=''> | + | <StructureSection load='4exg' size='340' side='right'caption='[[4exg]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4exg]] 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=4EXG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EXG FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4exg]] 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=4EXG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4EXG FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=916:N-[(2S,3R)-4-{[(4S)-6-(2,2-DIMETHYLPROPYL)-2,2-DIMETHYL-3,4-DIHYDRO-2H-THIENO[2,3-B]PYRAN-4-YL]AMINO}-3-HYDROXY-1-PHENYLBUTAN-2-YL]ACETAMIDE'>916</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=916:N-[(2S,3R)-4-{[(4S)-6-(2,2-DIMETHYLPROPYL)-2,2-DIMETHYL-3,4-DIHYDRO-2H-THIENO[2,3-B]PYRAN-4-YL]AMINO}-3-HYDROXY-1-PHENYLBUTAN-2-YL]ACETAMIDE'>916</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ewo|4ewo]]</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=4exg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4exg OCA], [https://pdbe.org/4exg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4exg RCSB], [https://www.ebi.ac.uk/pdbsum/4exg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4exg ProSAT]</span></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='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=4exg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4exg OCA], [http://pdbe.org/4exg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4exg RCSB], [http://www.ebi.ac.uk/pdbsum/4exg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4exg 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: Borkakoti, N]] | + | [[Category: Borkakoti N]] |
| - | [[Category: Derbyshire, D]] | + | [[Category: Derbyshire D]] |
| - | [[Category: Lindberg, J]] | + | [[Category: Lindberg J]] |
| - | [[Category: Aspartyl protease]]
| + | |
| - | [[Category: Bace]]
| + | |
| - | [[Category: Beta-secretase]]
| + | |
| - | [[Category: Glycoprotein]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Membrane]]
| + | |
| - | [[Category: Protease]]
| + | |
| - | [[Category: Statine]]
| + | |
| - | [[Category: Transmembrane]]
| + | |
| - | [[Category: Zymogen]]
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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 set of low molecular weight compounds containing a hydroxyethylamine (HEA) core structure with different prime side alkyl substituted 4,5,6,7-tetrahydrobenzazoles and one 4,5,6,7-tetrahydropyridinoazole was synthesized. Striking differences were observed on potencies in the BACE-1 enzymatic and cellular assays depending on the nature of the heteroatoms in the bicyclic ring, from the low active compound 4 to inhibitor 6, displaying BACE-1 IC(50) values of 44 nM (enzyme assay) and 65 nM (cell-based assay).
Design and synthesis of potent hydroxyethylamine (HEA) BACE-1 inhibitors carrying prime side 4,5,6,7-tetrahydrobenzazole and 4,5,6,7-tetrahydropyridinoazole templates.,Sund C, Belda O, Borkakoti N, Lindberg J, Derbyshire D, Vrang L, Hamelink E, Ahgren C, Woestenenk E, Wikstrom K, Eneroth A, Lindstrom E, Kalayanov G Bioorg Med Chem Lett. 2012 Nov 1;22(21):6721-7. doi: 10.1016/j.bmcl.2012.08.097. , Epub 2012 Sep 5. PMID:23010268[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
- ↑ Sund C, Belda O, Borkakoti N, Lindberg J, Derbyshire D, Vrang L, Hamelink E, Ahgren C, Woestenenk E, Wikstrom K, Eneroth A, Lindstrom E, Kalayanov G. Design and synthesis of potent hydroxyethylamine (HEA) BACE-1 inhibitors carrying prime side 4,5,6,7-tetrahydrobenzazole and 4,5,6,7-tetrahydropyridinoazole templates. Bioorg Med Chem Lett. 2012 Nov 1;22(21):6721-7. doi: 10.1016/j.bmcl.2012.08.097. , Epub 2012 Sep 5. PMID:23010268 doi:http://dx.doi.org/10.1016/j.bmcl.2012.08.097
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