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7b1p
From Proteopedia
(Difference between revisions)
(New page: '''Unreleased structure''' The entry 7b1p is ON HOLD Authors: Rondeau, J.M., Wirth, E. Description: Crystal Structure of Human BACE-1 in Complex with Compound 38a (NB-854) [[Category: ...) |
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal Structure of Human BACE-1 in Complex with Compound 38a (NB-854)== | |
| + | <StructureSection load='7b1p' size='340' side='right'caption='[[7b1p]], [[Resolution|resolution]] 1.77Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[7b1p]] 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=7B1P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7B1P 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]] 1.77Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SL8:~{N}-[3-[(3~{R},6~{R})-5-azanyl-3,6-dimethyl-6-(trifluoromethyl)-2~{H}-1,4-oxazin-3-yl]phenyl]-5-bromanyl-pyridine-2-carboxamide'>SL8</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=7b1p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7b1p OCA], [https://pdbe.org/7b1p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7b1p RCSB], [https://www.ebi.ac.uk/pdbsum/7b1p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7b1p 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 == | ||
| + | Starting from lead compound 4, the 1,4-oxazine headgroup was optimized to improve potency and brain penetration. Focusing at the 6-position of the 5-amino-1,4-oxazine, the insertion of a Me and a CF3 group delivered an excellent pharmacological profile with a pKa of 7.1 and a very low P-gp efflux ratio enabling high central nervous system (CNS) penetration and exposure. Various synthetic routes to access BACE1 inhibitors bearing a 5-amino-6-methyl-6-(trifluoromethyl)-1,4-oxazine headgroup were investigated. Subsequent optimization of the P3 fragment provided the highly potent N-(3-((3R,6R)-5-amino-3,6-dimethyl-6-(trifluoromethyl)-3,6-dihydro-2H-1,4-oxazin- 3-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide 54 (NB-360), able to reduce significantly Abeta levels in mice, rats, and dogs in acute and chronic treatment regimens. | ||
| - | + | Synthesis of the Potent, Selective, and Efficacious beta-Secretase (BACE1) Inhibitor NB-360.,Rueeger H, Lueoend R, Machauer R, Veenstra SJ, Holzer P, Hurth K, Voegtle M, Frederiksen M, Rondeau JM, Tintelnot-Blomley M, Jacobson LH, Staufenbiel M, Laue G, Neumann U J Med Chem. 2021 Apr 22;64(8):4677-4696. doi: 10.1021/acs.jmedchem.0c02143. Epub , 2021 Apr 12. PMID:33844524<ref>PMID:33844524</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 7b1p" style="background-color:#fffaf0;"></div> |
| - | [[Category: Rondeau | + | |
| + | ==See Also== | ||
| + | *[[Beta secretase 3D structures|Beta secretase 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Rondeau JM]] | ||
| + | [[Category: Wirth E]] | ||
Current revision
Crystal Structure of Human BACE-1 in Complex with Compound 38a (NB-854)
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