View source for 4rce


==Crystal structure of BACE1 in complex with aminooxazoline xanthene inhibitor 2==
<StructureSection load='4rce' size='340' side='right'caption='[[4rce]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4rce]] 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=4RCE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RCE 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]] 2.4&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3LN:(4S)-2-(2,2-DIMETHYLPROPOXY)-7-(PYRIMIDIN-5-YL)SPIRO[1,3-OXAZOLE-4,9-XANTHEN]-2-AMINE'>3LN</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=4rce FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rce OCA], [https://pdbe.org/4rce PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4rce RCSB], [https://www.ebi.ac.uk/pdbsum/4rce PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4rce 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 ==
The optimization of a series of aminooxazoline xanthene inhibitors of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust Abeta lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardiovascular models consistent with in vitro activity on the hERG ion channel. While the introduction of polar groups was effective in reducing hERG binding affinity, this came at the expense of higher than desired Pgp-mediated efflux. A balance of low Pgp efflux and hERG activity was achieved by lowering the polar surface area of the P3 substituent while retaining polarity in the P2' side chain. The introduction of a fluorine in position 4 of the xanthene ring improved BACE1 potency (5-10-fold). The combination of these optimized fragments resulted in identification of compound 40, which showed robust Abeta reduction in a rat pharmacodynamic model (78% Abeta reduction in CSF at 10 mg/kg po) and also showed acceptable cardiovascular safety in vivo.

Lead Optimization and Modulation of hERG Activity in a Series of Aminooxazoline Xanthene beta-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors.,Epstein O, Bryan MC, Cheng AC, Derakhchan K, Dineen TA, Hickman D, Hua Z, Human JB, Kreiman C, Marx IE, Weiss MM, Wahl RC, Wen PH, Whittington DA, Wood S, Zheng XM, Fremeau RT Jr, White RD, Patel VF J Med Chem. 2014 Dec 11;57(23):9796-810. doi: 10.1021/jm501266w. Epub 2014 Nov, 12. PMID:25389560<ref>PMID:25389560</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4rce" 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: Long AM]]
[[Category: Whittington DA]]