7d5u: Difference between revisions
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==== | ==BACE2 xaperone complex with N-{3-[(9S)-7-amino-2,2-difluoro-9-(prop-1-yn-1-yl)-6-oxa-8-azaspiro[3.5]non-7-en-9-yl]-4-fluorophenyl}-5-cyanopyridine-2-carboxamide== | ||
<StructureSection load='7d5u' size='340' side='right'caption='[[7d5u]]' scene=''> | <StructureSection load='7d5u' size='340' side='right'caption='[[7d5u]], [[Resolution|resolution]] 2.04Å' 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= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br> | <table><tr><td colspan='2'>[[7d5u]] is a 2 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=7D5U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7D5U 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=7d5u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7d5u OCA], [https://pdbe.org/7d5u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7d5u RCSB], [https://www.ebi.ac.uk/pdbsum/7d5u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7d5u 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]] 2.04Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GX6:~{N}-[3-[(9~{S})-7-azanyl-2,2-bis(fluoranyl)-9-prop-1-ynyl-6-oxa-8-azaspiro[3.5]non-7-en-9-yl]-4-fluoranyl-phenyl]-5-cyano-pyridine-2-carboxamide'>GX6</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=7d5u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7d5u OCA], [https://pdbe.org/7d5u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7d5u RCSB], [https://www.ebi.ac.uk/pdbsum/7d5u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7d5u ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
BACE1 is an attractive target for disease-modifying treatment of Alzheimer's disease. BACE2, having high homology around the catalytic site, poses a critical challenge to identifying selective BACE1 inhibitors. Recent evidence indicated that BACE2 has various roles in peripheral tissues and the brain, and therefore, the chronic use of nonselective inhibitors may cause side effects derived from BACE2 inhibition. Crystallographic analysis of the nonselective inhibitor verubecestat identified explicit water molecules with different levels of free energy in the S2' pocket. Structure-based design targeting them enabled the identification of propynyl oxazine 3 with improved selectivity. Further optimization efforts led to the discovery of compound 6 with high selectivity. The cocrystal structures of 7, a close analogue of 6, bound to BACE1 and BACE2 confirmed that one of the explicit water molecules is displaced by the propynyl group, suggesting that the difference in the relative water displacement cost may contribute to the improved selectivity. | |||
Structure-Based Approaches to Improving Selectivity through Utilizing Explicit Water Molecules: Discovery of Selective beta-Secretase (BACE1) Inhibitors over BACE2.,Fujimoto K, Yoshida S, Tadano G, Asada N, Fuchino K, Suzuki S, Matsuoka E, Yamamoto T, Yamamoto S, Ando S, Kanegawa N, Tonomura Y, Ito H, Moechars D, Rombouts FJR, Gijsen HJM, Kusakabe KI J Med Chem. 2021 Mar 25;64(6):3075-3085. doi: 10.1021/acs.jmedchem.0c01858. Epub , 2021 Mar 15. PMID:33719429<ref>PMID:33719429</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7d5u" 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: | [[Category: Ando S]] | ||
[[Category: Asada N]] | |||
[[Category: Fuchino K]] | |||
[[Category: Fujimoto K]] | |||
[[Category: Gijsen HJM]] | |||
[[Category: Ito H]] | |||
[[Category: Kanegawa N]] | |||
[[Category: Kusakabe KI]] | |||
[[Category: Matsuoka E]] | |||
[[Category: Moechars D]] | |||
[[Category: Rombouts FJR]] | |||
[[Category: Suzuki S]] | |||
[[Category: Tadano G]] | |||
[[Category: Tonomura Y]] | |||
[[Category: Yamamoto S]] | |||
[[Category: Yamamoto T]] | |||
[[Category: Yoshida S]] | |||