7f1d
From Proteopedia
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==Crystal Structure of BACE1 in complex with N-{3-[(4R,5R,6R)-2-amino-5-fluoro-4,6-dimethyl-5,6-dihydro-4H-1,3-thiazin-4-yl]-4-fluorophenyl}-2H,3H-[1,4]dioxino[2,3-c]pyridine-7-carboxamide== | ==Crystal Structure of BACE1 in complex with N-{3-[(4R,5R,6R)-2-amino-5-fluoro-4,6-dimethyl-5,6-dihydro-4H-1,3-thiazin-4-yl]-4-fluorophenyl}-2H,3H-[1,4]dioxino[2,3-c]pyridine-7-carboxamide== | ||
| - | <StructureSection load='7f1d' size='340' side='right'caption='[[7f1d]]' scene=''> | + | <StructureSection load='7f1d' size='340' side='right'caption='[[7f1d]], [[Resolution|resolution]] 2.05Å' 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=7F1D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7F1D FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7f1d]] 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=7F1D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7F1D 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=7f1d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7f1d OCA], [https://pdbe.org/7f1d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7f1d RCSB], [https://www.ebi.ac.uk/pdbsum/7f1d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7f1d 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]] 2.05Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0QQ:N-[3-[(4R,5R,6R)-2-azanyl-5-fluoranyl-4,6-dimethyl-5,6-dihydro-1,3-thiazin-4-yl]-4-fluoranyl-phenyl]-2,3-dihydro-[1,4]dioxino[2,3-c]pyridine-7-carboxamide'>0QQ</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=7f1d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7f1d OCA], [https://pdbe.org/7f1d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7f1d RCSB], [https://www.ebi.ac.uk/pdbsum/7f1d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7f1d 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) is considered to be a promising target for treating Alzheimer's disease. However, all clinical BACE1 inhibitors have failed due to lack of efficacy, and some have even led to cognitive worsening. Recent evidence points to the importance of avoiding BACE2 inhibition along with careful dose titration. In this study, we focused on the fact that the 10s loop lining the S3 pocket in BACE1 can form both "open (up)" and "closed (down)" conformations, whereas in BACE2, it prefers to adopt a "closed" form; thus, more space is available in BACE1. By leveraging the difference, we designed fused pyridine analogues that could reach the 10s loop, leading to 6 with high selectivity and significant Abeta reduction. The cocrystal structures confirmed that 6 significantly increased B-factors of the 10s loop in BACE2 relative to those in BACE1. Thus, the destabilization of BACE2 seems to offer structural insights into the reduced BACE2 potency of 6, explaining the significant improvement in BACE1 selectivity. | ||
| + | |||
| + | Discovery of Extremely Selective Fused Pyridine-Derived beta-Site Amyloid Precursor Protein-Cleaving Enzyme (BACE1) Inhibitors with High In Vivo Efficacy through 10s Loop Interactions.,Ueno T, Matsuoka E, Asada N, Yamamoto S, Kanegawa N, Ito M, Ito H, Moechars D, Rombouts FJR, Gijsen HJM, Kusakabe KI J Med Chem. 2021 Oct 14;64(19):14165-14174. doi: 10.1021/acs.jmedchem.1c00359., Epub 2021 Sep 23. PMID:34553947<ref>PMID:34553947</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7f1d" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==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: Asada N]] | [[Category: Asada N]] | ||
Revision as of 17:07, 29 November 2023
Crystal Structure of BACE1 in complex with N-{3-[(4R,5R,6R)-2-amino-5-fluoro-4,6-dimethyl-5,6-dihydro-4H-1,3-thiazin-4-yl]-4-fluorophenyl}-2H,3H-[1,4]dioxino[2,3-c]pyridine-7-carboxamide
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Categories: Homo sapiens | Large Structures | Asada N | Gijsen HJM | Ito H | Ito M | Kanegawa N | Kusakabe KI | Matsuoka E | Moechars D | Rombouts FJR | Ueno T | Yamamoto S
