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| | <StructureSection load='3pi5' size='340' side='right'caption='[[3pi5]], [[Resolution|resolution]] 2.40Å' scene=''> | | <StructureSection load='3pi5' size='340' side='right'caption='[[3pi5]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3pi5]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3PI5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3PI5 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3pi5]] is a 3 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=3PI5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3PI5 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3P5:(3S,4S,5R)-3-(3-BROMO-4-HYDROXYBENZYL)-5-[(3-CYCLOPROPYLBENZYL)AMINO]TETRAHYDRO-2H-THIOPYRAN-4-OL+1,1-DIOXIDE'>3P5</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]] 2.4Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE, BACE1, KIAA1149 ([https://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=3P5:(3S,4S,5R)-3-(3-BROMO-4-HYDROXYBENZYL)-5-[(3-CYCLOPROPYLBENZYL)AMINO]TETRAHYDRO-2H-THIOPYRAN-4-OL+1,1-DIOXIDE'>3P5</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [https://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=3pi5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3pi5 OCA], [https://pdbe.org/3pi5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3pi5 RCSB], [https://www.ebi.ac.uk/pdbsum/3pi5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3pi5 ProSAT]</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=3pi5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3pi5 OCA], [https://pdbe.org/3pi5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3pi5 RCSB], [https://www.ebi.ac.uk/pdbsum/3pi5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3pi5 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[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>
| + | [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: Rondeau JM]] |
| - | [[Category: Rondeau, J M]] | + | |
| - | [[Category: Aspartic proteinase]]
| + | |
| - | [[Category: Enzyme inhibitor complex]]
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| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
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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
This Letter describes the de novo design of non-peptidic hydroxyethylamine (HEA) inhibitors of BACE-1 by elimination of P-gp contributing amide attachments. The predicted binding mode of the novel cyclic sulfone HEA core template was confirmed in a X-ray co-crystal structure. Inhibitors of sub-micromolar potency with an improved property profile over historic HEA inhibitors resulting in improved brain penetration are described.
Structure based design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors.,Rueeger H, Rondeau JM, McCarthy C, Mobitz H, Tintelnot-Blomley M, Neumann U, Desrayaud S Bioorg Med Chem Lett. 2011 Apr 1;21(7):1942-7. Epub 2011 Feb 15. PMID:21388807[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
- ↑ Rueeger H, Rondeau JM, McCarthy C, Mobitz H, Tintelnot-Blomley M, Neumann U, Desrayaud S. Structure based design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors. Bioorg Med Chem Lett. 2011 Apr 1;21(7):1942-7. Epub 2011 Feb 15. PMID:21388807 doi:10.1016/j.bmcl.2011.02.038
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