4zsq: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==BACE crystal structure with tricyclic aminothiazine inhibitor== | ==BACE crystal structure with tricyclic aminothiazine inhibitor== | ||
<StructureSection load='4zsq' size='340' side='right' caption='[[4zsq]], [[Resolution|resolution]] 2.30Å' scene=''> | <StructureSection load='4zsq' size='340' side='right'caption='[[4zsq]], [[Resolution|resolution]] 2.30Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4zsq]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZSQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZSQ FirstGlance]. <br> | <table><tr><td colspan='2'>[[4zsq]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZSQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZSQ FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4RX:N-[(4S,4AS,6S,8AR)-10-AMINOHEXAHYDRO-3H-4,8A-(EPITHIOMETHENOAZENO)ISOCHROMEN-6(1H)-YL]-3-CHLOROBENZAMIDE'>4RX</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4RX:N-[(4S,4AS,6S,8AR)-10-AMINOHEXAHYDRO-3H-4,8A-(EPITHIOMETHENOAZENO)ISOCHROMEN-6(1H)-YL]-3-CHLOROBENZAMIDE'>4RX</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4zsm|4zsm]], [[4zsp|4zsp]], [[4zsr|4zsr]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4zsm|4zsm]], [[4zsp|4zsp]], [[4zsr|4zsr]]</td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE1, BACE, KIAA1149 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] </span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4zsq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zsq OCA], [http://pdbe.org/4zsq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zsq RCSB], [http://www.ebi.ac.uk/pdbsum/4zsq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zsq ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4zsq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zsq OCA], [http://pdbe.org/4zsq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zsq RCSB], [http://www.ebi.ac.uk/pdbsum/4zsq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zsq ProSAT]</span></td></tr> | ||
| Line 20: | Line 21: | ||
</div> | </div> | ||
<div class="pdbe-citations 4zsq" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 4zsq" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Beta secretase 3D structures|Beta secretase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Memapsin 2]] | [[Category: Memapsin 2]] | ||
[[Category: Timm, D E]] | [[Category: Timm, D E]] | ||
Revision as of 11:27, 26 June 2019
BACE crystal structure with tricyclic aminothiazine inhibitorBACE crystal structure with tricyclic aminothiazine inhibitor
Structural highlights
Function[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.[1] [2] Publication Abstract from PubMedThe BACE1 enzyme is a key target for Alzheimer's disease. During our BACE1 research efforts, fragment screening revealed that bicyclic thiazine 3 had low millimolar activity against BACE1. Analysis of the co-crystal structure of 3 suggested that potency could be increased through extension toward the S3 pocket and through conformational constraint of the thiazine core. Pursuit of S3-binding groups produced low micromolar inhibitor 6, which informed the S3-design for constrained analogs 7 and 8, themselves prepared via independent, multi-step synthetic routes. Biological characterization of BACE inhibitors 6-8 is described. Preparation and biological evaluation of conformationally constrained BACE1 inhibitors.,Winneroski LL, Schiffler MA, Erickson JA, May PC, Monk SA, Timm DE, Audia JE, Beck JP, Boggs LN, Borders AR, Boyer RD, Brier RA, Hudziak KJ, Klimkowski VJ, Garcia Losada P, Mathes BM, Stout SL, Watson BM, Mergott DJ Bioorg Med Chem. 2015 Jul 1;23(13):3260-8. doi: 10.1016/j.bmc.2015.04.062. Epub, 2015 May 6. PMID:26001341[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||||||