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| | ==Crystal Structure of Human Beta Secretase in Complex with compound 11d== | | ==Crystal Structure of Human Beta Secretase in Complex with compound 11d== |
| - | <StructureSection load='4lxk' size='340' side='right' caption='[[4lxk]], [[Resolution|resolution]] 2.05Å' scene=''> | + | <StructureSection load='4lxk' size='340' side='right'caption='[[4lxk]], [[Resolution|resolution]] 2.05Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4lxk]] is a 3 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=4LXK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4LXK FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4lxk]] 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=4LXK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4LXK FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1YT:(1R,3S,4S,5R)-3-(4-AMINO-3-FLUORO-5-{[(2R)-1,1,1-TRIFLUORO-3-METHOXYPROPAN-2-YL]OXY}BENZYL)-5-[(3-TERT-BUTYLBENZYL)AMINO]TETRAHYDRO-2H-THIOPYRAN-4-OL+1-OXIDE'>1YT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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]] 2.05Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4lxa|4lxa]], [[4lxm|4lxm]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1YT:(1R,3S,4S,5R)-3-(4-AMINO-3-FLUORO-5-{[(2R)-1,1,1-TRIFLUORO-3-METHOXYPROPAN-2-YL]OXY}BENZYL)-5-[(3-TERT-BUTYLBENZYL)AMINO]TETRAHYDRO-2H-THIOPYRAN-4-OL+1-OXIDE'>1YT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4lxk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lxk OCA], [https://pdbe.org/4lxk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4lxk RCSB], [https://www.ebi.ac.uk/pdbsum/4lxk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4lxk ProSAT]</span></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=4lxk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lxk OCA], [http://pdbe.org/4lxk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4lxk RCSB], [http://www.ebi.ac.uk/pdbsum/4lxk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4lxk 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: Bourgier, E]] | + | [[Category: Bourgier E]] |
| - | [[Category: Rondeau, J M]] | + | [[Category: Rondeau JM]] |
| - | [[Category: Aspartyl protease]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
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| - | [[Category: Membrane]]
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| - | [[Category: Structure-based drug design]]
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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
Previous structure based optimization in our laboratories led to the identification of a novel, high-affinity cyclic sulfone hydroxyethylamine-derived inhibitor such as 1 that lowers CNS-derived Abeta following oral administration to transgenic APP51/16 mice. Herein we report SAR development in the S3 and S2' subsites of BACE1 for cyclic sulfoxide hydroxyethyl amine inhibitors, the synthetic approaches employed in this effort, and in vivo data for optimized compound such as 11d.
Discovery of cyclic sulfoxide hydroxyethylamines as potent and selective beta-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure based design and in vivo reduction of amyloid beta-peptides.,Rueeger H, Lueoend R, Machauer R, Veenstra SJ, Jacobson LH, Staufenbiel M, Desrayaud S, Rondeau JM, Mobitz H, Neumann U Bioorg Med Chem Lett. 2013 Oct 1;23(19):5300-6. doi: 10.1016/j.bmcl.2013.07.071. , Epub 2013 Aug 9. PMID:23981898[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, Lueoend R, Machauer R, Veenstra SJ, Jacobson LH, Staufenbiel M, Desrayaud S, Rondeau JM, Mobitz H, Neumann U. Discovery of cyclic sulfoxide hydroxyethylamines as potent and selective beta-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure based design and in vivo reduction of amyloid beta-peptides. Bioorg Med Chem Lett. 2013 Oct 1;23(19):5300-6. doi: 10.1016/j.bmcl.2013.07.071. , Epub 2013 Aug 9. PMID:23981898 doi:http://dx.doi.org/10.1016/j.bmcl.2013.07.071
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