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| | <StructureSection load='4rcd' size='340' side='right'caption='[[4rcd]], [[Resolution|resolution]] 1.90Å' scene=''> | | <StructureSection load='4rcd' size='340' side='right'caption='[[4rcd]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4rcd]] 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=4RCD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RCD FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4rcd]] 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=4RCD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RCD FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3LL:(5S)-7-(2-FLUOROPYRIDIN-3-YL)-3-[(3-METHYLOXETAN-3-YL)ETHYNYL]SPIRO[CHROMENO[2,3-B]PYRIDINE-5,4-[1,3]OXAZOL]-2-AMINE'>3LL</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=3LL:(5S)-7-(2-FLUOROPYRIDIN-3-YL)-3-[(3-METHYLOXETAN-3-YL)ETHYNYL]SPIRO[CHROMENO[2,3-B]PYRIDINE-5,4-[1,3]OXAZOL]-2-AMINE'>3LL</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">[[4rce|4rce]], [[4rcf|4rcf]]</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=4rcd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rcd OCA], [https://pdbe.org/4rcd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4rcd RCSB], [https://www.ebi.ac.uk/pdbsum/4rcd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4rcd 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=4rcd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rcd OCA], [http://pdbe.org/4rcd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4rcd RCSB], [http://www.ebi.ac.uk/pdbsum/4rcd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4rcd 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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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Memapsin 2]]
| + | [[Category: Long AM]] |
| - | [[Category: Long, A M]] | + | [[Category: Whittington DA]] |
| - | [[Category: Whittington, D A]] | + | |
| - | [[Category: Alzheimer's disease]]
| + | |
| - | [[Category: Amyloid precursor protein]]
| + | |
| - | [[Category: App]]
| + | |
| - | [[Category: Aspartyl protease]]
| + | |
| - | [[Category: Brain]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| 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
We have previously shown that the aminooxazoline xanthene scaffold can generate potent and orally efficacious BACE1 inhibitors although certain of these compounds exhibited potential hERG liabilities. In this article, we describe 4-aza substitution on the xanthene core as a means to increase BACE1 potency while reducing hERG binding affinity. Further optimization of the P3 and P2' side chains resulted in the identification of 42 (AMG-8718), a compound with a balanced profile of BACE1 potency, hERG binding affinity, and Pgp recognition. This compound produced robust and sustained reductions of CSF and brain Abeta levels in a rat pharmacodynamic model and exhibited significantly reduced potential for QTc elongation in a cardiovascular safety model.
Inhibitors of beta-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1): Identification of (S)-7-(2-Fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5'H-spiro[chromeno[ 2,3-b]pyridine-5,4'-oxazol]-2'-amine (AMG-8718).,Dineen TA, Chen K, Cheng AC, Derakhchan K, Epstein O, Esmay J, Hickman D, Kreiman CE, Marx IE, Wahl RC, Wen PH, Weiss MM, Whittington DA, Wood S, Fremeau RT Jr, White RD, Patel VF J Med Chem. 2014 Dec 11;57(23):9811-31. doi: 10.1021/jm5012676. Epub 2014 Nov 14. PMID:25363711[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
- ↑ Dineen TA, Chen K, Cheng AC, Derakhchan K, Epstein O, Esmay J, Hickman D, Kreiman CE, Marx IE, Wahl RC, Wen PH, Weiss MM, Whittington DA, Wood S, Fremeau RT Jr, White RD, Patel VF. Inhibitors of beta-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1): Identification of (S)-7-(2-Fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5'H-spiro[chromeno[ 2,3-b]pyridine-5,4'-oxazol]-2'-amine (AMG-8718). J Med Chem. 2014 Dec 11;57(23):9811-31. doi: 10.1021/jm5012676. Epub 2014 Nov 14. PMID:25363711 doi:http://dx.doi.org/10.1021/jm5012676
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