7d2x: Difference between revisions

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OCA

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-'''Unreleased structure'''
-The entry 7d2x is ON HOLD
+==Crystal Structure of BACE1 in complex with N-{3-[(4R)-2-amino-4-(prop-1-yn-1-yl)-5,6-dihydro-4H-1,3-oxazin-4-yl]-4-fluorophenyl}-5-cyanopyridine-2-carboxamide==
+<StructureSection load='7d2x' size='340' side='right'caption='[[7d2x]], [[Resolution|resolution]] 2.45&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[7d2x]] 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=7D2X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7D2X FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.45&#8491;</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=GTU:N-[3-[(4R)-2-azanyl-4-prop-1-ynyl-5,6-dihydro-1,3-oxazin-4-yl]-4-fluoranyl-phenyl]-5-cyano-pyridine-2-carboxamide'>GTU</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=7d2x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7d2x OCA], [https://pdbe.org/7d2x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7d2x RCSB], [https://www.ebi.ac.uk/pdbsum/7d2x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7d2x ProSAT]</span></td></tr>
+</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 ==
+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.
-Authors: 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, F.J.R., Gijsen, H.J.M., Kusakabe, K.I.
+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>
-Description: Crystal Structure of BACE1 in complex with N-{3-[(4R)-2-amino-4-(prop-1-yn-1-yl)-5,6-dihydro-4H-1,3-oxazin-4-yl]-4-fluorophenyl}-5-cyanopyridine-2-carboxamide
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Yamamoto, T]]
+<div class="pdbe-citations 7d2x" style="background-color:#fffaf0;"></div>
-[[Category: Fujimoto, K]]
-[[Category: Yamamoto, S]]
+==See Also==
-[[Category: Suzuki, S]]
+*[[Beta secretase 3D structures|Beta secretase 3D structures]]
-[[Category: Rombouts, F.J.R]]
+== References ==
-[[Category: Tonomura, Y]]
+<references/>
-[[Category: Tadano, G]]
+__TOC__
-[[Category: Asada, N]]
+</StructureSection>
-[[Category: Ando, S]]
+[[Category: Homo sapiens]]
-[[Category: Kusakabe, K.I]]
+[[Category: Large Structures]]
-[[Category: Fuchino, K]]
+[[Category: Ando S]]
-[[Category: Moechars, D]]
+[[Category: Asada N]]
-[[Category: Yoshida, S]]
+[[Category: Fuchino K]]
-[[Category: Ito, H]]
+[[Category: Fujimoto K]]
-[[Category: Gijsen, H.J.M]]
+[[Category: Gijsen HJM]]
-[[Category: Matsuoka, E]]
+[[Category: Ito H]]
-[[Category: Kanegawa, N]]
+[[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]]