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==CRYSTAL STRUCTURE OF BACE-1 IN COMPLEX WITH 5-Cyano-pyridine-2-carboxylic acid [3-((4R,5R,6S)-2-amino-5-fluoro-4-methyl-6-trifluoromethyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-amide== | ==CRYSTAL STRUCTURE OF BACE-1 IN COMPLEX WITH 5-Cyano-pyridine-2-carboxylic acid [3-((4R,5R,6S)-2-amino-5-fluoro-4-methyl-6-trifluoromethyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-amide== | ||
<StructureSection load='4j1k' size='340' side='right' caption='[[4j1k]], [[Resolution|resolution]] 2.18Å' scene=''> | <StructureSection load='4j1k' size='340' side='right'caption='[[4j1k]], [[Resolution|resolution]] 2.18Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4j1k]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4j1k]] 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=4J1K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4J1K FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1HG:N-{3-[(4R,5R,6S)-2-AMINO-5-FLUORO-4-METHYL-6-(TRIFLUOROMETHYL)-5,6-DIHYDRO-4H-1,3-OXAZIN-4-YL]-4-FLUOROPHENYL}-5-CYANOPYRIDINE-2-CARBOXAMIDE'>1HG</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.18Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1HG:N-{3-[(4R,5R,6S)-2-AMINO-5-FLUORO-4-METHYL-6-(TRIFLUOROMETHYL)-5,6-DIHYDRO-4H-1,3-OXAZIN-4-YL]-4-FLUOROPHENYL}-5-CYANOPYRIDINE-2-CARBOXAMIDE'>1HG</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></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=4j1k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4j1k OCA], [https://pdbe.org/4j1k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4j1k RCSB], [https://www.ebi.ac.uk/pdbsum/4j1k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4j1k ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</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> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 23: | Line 21: | ||
==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: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Kuglstatter | [[Category: Kuglstatter A]] | ||
[[Category: Stihle | [[Category: Stihle M]] | ||
Latest revision as of 10:04, 27 November 2024
CRYSTAL STRUCTURE OF BACE-1 IN COMPLEX WITH 5-Cyano-pyridine-2-carboxylic acid [3-((4R,5R,6S)-2-amino-5-fluoro-4-methyl-6-trifluoromethyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-amideCRYSTAL STRUCTURE OF BACE-1 IN COMPLEX WITH 5-Cyano-pyridine-2-carboxylic acid [3-((4R,5R,6S)-2-amino-5-fluoro-4-methyl-6-trifluoromethyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-amide
Structural highlights
FunctionBACE1_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 PubMedAn extensive fluorine scan of 1,3-oxazines revealed the power of fluorine(s) to lower the pKa and thereby dramatically change the pharmacological profile of this class of BACE1 inhibitors. The CF3 substituted oxazine 89, a potent and highly brain penetrant BACE1 inhibitor, was able to reduce significantly CSF Abeta40 & 42 in rats at oral doses as low as 1 mg/kg. The effect was long lasting, showing a significant reduction of Abeta40 & 42 even after 24 h. In contrast to 89, compound 1b lacking the CF3 group was virtually inactive in vivo. beta-Secretase (BACE1) Inhibitors with High In Vivo Efficacy Suitable for Clinical Evaluation in Alzheimer's Disease.,Hilpert H, Guba W, Woltering TJ, Wostl W, Pinard E, Mauser H, Mayweg AV, Rogers-Evans M, Humm R, Krummenacher D, Muser T, Schnider C, Jacobsen H, Ozmen L, Bergadano A, Banner DW, Hochstrasser R, Kuglstatter A, David-Pierson P, Fischer H, Polara A, Narquizian R J Med Chem. 2013 Apr 16. PMID:23590342[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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