6bfw: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==BACE crystal structure with hydroxy morpholine inhibitor== | ==BACE crystal structure with hydroxy morpholine inhibitor== | ||
<StructureSection load='6bfw' size='340' side='right' caption='[[6bfw]], [[Resolution|resolution]] 1.84Å' scene=''> | <StructureSection load='6bfw' size='340' side='right'caption='[[6bfw]], [[Resolution|resolution]] 1.84Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6bfw]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[6bfw]] 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=6BFW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6BFW FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DK7:N-[(1S,2S)-1-[(3R,6R)-6-(cyclohexylmethoxy)morpholin-3-yl]-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl]acetamide'>DK7</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.84Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DK7:N-[(1S,2S)-1-[(3R,6R)-6-(cyclohexylmethoxy)morpholin-3-yl]-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl]acetamide'>DK7</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=6bfw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bfw OCA], [https://pdbe.org/6bfw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6bfw RCSB], [https://www.ebi.ac.uk/pdbsum/6bfw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6bfw ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == 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;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 20: | Line 19: | ||
</div> | </div> | ||
<div class="pdbe-citations 6bfw" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 6bfw" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Beta secretase 3D structures|Beta secretase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Timm | [[Category: Timm DE]] | ||
Latest revision as of 15:28, 6 November 2024
BACE crystal structure with hydroxy morpholine inhibitorBACE crystal structure with hydroxy morpholine inhibitor
Structural highlights
FunctionBACE1_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 PubMedNMR Conformational analysis of a hydroxyethylamine peptide isostere developed as an aspartyl protease inhibitor shows that it is a flexible architecture. Cyclization to form pyrrolidines, piperidines or morpholines results in a preorganization of the whole system in solution. The resulting conformation is similar to the conformation of the inhibitor in the active site of BACE-1. This entropic gain results in increased affinity for the enzyme when compared with the acyclic system. For morpholines 27 and 29, the combination of steric and electronic factors is exploited to orient substituents toward S1, S1' and S2' pockets both in the solution and in the bound states. These highly preorganized molecules proved to be the most potent compounds of the series. Additionally, the morpholines, unlike the pyrrolidine and piperidine analogs, have been found to be brain penetrant BACE-1 inhibitors. Optimization of Hydroxyethylamine Transition State Isosteres as Aspartic Protease Inhibitors by Exploiting Conformational Preferences.,Bueno AB, Agejas J, Broughton HB, Dally R, Durham T, Espinosa JF, Gonzalez R, Hahn PJ, Marcos A, Rodriguez R, Sanz G, Soriano J, Timm DE, Vidal P, Yang HC, McCarthy J J Med Chem. 2017 Oct 31. doi: 10.1021/acs.jmedchem.7b01304. PMID:29088532[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||