7d36
From Proteopedia
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==Crystal Structure of BACE1 in complex with N-{3-[(3S)-1-amino-5-fluoro-3-methyl-3,4-dihydro-2,6-naphthyridin-3-yl]-4-fluorophenyl}-5-cyano-3-methylpyridine-2-carboxamide== | ==Crystal Structure of BACE1 in complex with N-{3-[(3S)-1-amino-5-fluoro-3-methyl-3,4-dihydro-2,6-naphthyridin-3-yl]-4-fluorophenyl}-5-cyano-3-methylpyridine-2-carboxamide== | ||
| - | <StructureSection load='7d36' size='340' side='right'caption='[[7d36]]' scene=''> | + | <StructureSection load='7d36' size='340' side='right'caption='[[7d36]], [[Resolution|resolution]] 2.30Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7D36 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7D36 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7d36]] 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=7D36 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7D36 FirstGlance]. <br> |
| - | </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=7d36 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7d36 OCA], [https://pdbe.org/7d36 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7d36 RCSB], [https://www.ebi.ac.uk/pdbsum/7d36 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7d36 ProSAT]</span></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]] 2.3Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=GUC:N-[3-[(3S)-1-azanyl-5-fluoranyl-3-methyl-4H-2,6-naphthyridin-3-yl]-4-fluoranyl-phenyl]-5-cyano-3-methyl-pyridine-2-carboxamide'>GUC</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</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=7d36 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7d36 OCA], [https://pdbe.org/7d36 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7d36 RCSB], [https://www.ebi.ac.uk/pdbsum/7d36 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7d36 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == 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;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | beta-Site amyloid precursor protein cleaving enzyme 1 (BACE1) has been pursued as a prime target for the treatment of Alzheimer's disease (AD). In this report, we describe the discovery of BACE1 inhibitors with a 1-amino-3,4-dihydro-2,6-naphthyridine scaffold. Leveraging known inhibitors 2a and 2b, we designed the naphthyridine-based compounds by removing a structurally labile moiety and incorporating pyridine rings, which showed increased biochemical and cellular potency, along with reduced basicity on the amidine moiety. Introduction of a fluorine atom on the pyridine culminated in compound 11 which had improved cellular activity as well as further reduced basicity and demonstrated a robust and sustained cerebrospinal fluid (CSF) Abeta reduction in dog. The crystal structure of compound 11 bound to BACE1 confirmed van der Waals interactions between the fluorine on the pyridine and Tyr71 in the flap. | ||
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| + | Balancing potency and basicity by incorporating fluoropyridine moieties: Discovery of a 1-amino-3,4-dihydro-2,6-naphthyridine BACE1 inhibitor that affords robust and sustained central Abeta reduction.,Nakahara K, Mitsuoka Y, Kasuya S, Yamamoto T, Yamamoto S, Ito H, Kido Y, Kusakabe KI Eur J Med Chem. 2021 Apr 15;216:113270. doi: 10.1016/j.ejmech.2021.113270. Epub, 2021 Feb 7. PMID:33765486<ref>PMID:33765486</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7d36" style="background-color:#fffaf0;"></div> | ||
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| + | ==See Also== | ||
| + | *[[Beta secretase 3D structures|Beta secretase 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Ito H]] | [[Category: Ito H]] | ||
Current revision
Crystal Structure of BACE1 in complex with N-{3-[(3S)-1-amino-5-fluoro-3-methyl-3,4-dihydro-2,6-naphthyridin-3-yl]-4-fluorophenyl}-5-cyano-3-methylpyridine-2-carboxamide
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Categories: Homo sapiens | Large Structures | Ito H | Kasuya S | Kido Y | Kusakabe KI | Mitsuoka Y | Nakahara K | Yamamoto S | Yamamoto T
