4rcd: Difference between revisions
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==Crystal structure of BACE1 in complex with a 2-aminooxazoline 4-azaxanthene inhibitor== | ==Crystal structure of BACE1 in complex with a 2-aminooxazoline 4-azaxanthene inhibitor== | ||
<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. 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 [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> | ||
</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"><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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4rce|4rce]], [[4rcf|4rcf]]</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='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> | <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> | ||
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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: Large Structures]] | |||
[[Category: Memapsin 2]] | [[Category: Memapsin 2]] | ||
[[Category: Long, A M]] | [[Category: Long, A M]] | ||
Revision as of 12:49, 1 May 2019
Crystal structure of BACE1 in complex with a 2-aminooxazoline 4-azaxanthene inhibitorCrystal structure of BACE1 in complex with a 2-aminooxazoline 4-azaxanthene inhibitor
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 PubMedWe 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 AlsoReferences
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