View source for 6bfd


==BACE crystal structure with hydroxy pyrrolidine inhibitor==
<StructureSection load='6bfd' size='340' side='right'caption='[[6bfd]], [[Resolution|resolution]] 1.62&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6bfd]] 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=6BFD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6BFD 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]] 1.62&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DJS:2-{[(2S)-butan-2-yl]amino}-N-{(1R,2S)-1-hydroxy-3-phenyl-1-[(2R)-pyrrolidin-2-yl]propan-2-yl}-6-(methylsulfonyl)pyridine-4-carboxamide'>DJS</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=6bfd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bfd OCA], [https://pdbe.org/6bfd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6bfd RCSB], [https://www.ebi.ac.uk/pdbsum/6bfd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6bfd 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 ==
NMR 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<ref>PMID:29088532</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6bfd" style="background-color:#fffaf0;"></div>

==See Also==
*[[Beta secretase 3D structures|Beta secretase 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Timm DE]]