5ux4
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==Crystal Structure of Rat Cathepsin D with (5S)-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro- 7-(2-fluoropyridin-3-yl)spiro[chromeno[2,3- c]pyridine-5,4'-[1,3]oxazol]-2'-amine== | ==Crystal Structure of Rat Cathepsin D with (5S)-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro- 7-(2-fluoropyridin-3-yl)spiro[chromeno[2,3- c]pyridine-5,4'-[1,3]oxazol]-2'-amine== | ||
| - | <StructureSection load='5ux4' size='340' side='right' caption='[[5ux4]], [[Resolution|resolution]] 2.81Å' scene=''> | + | <StructureSection load='5ux4' size='340' side='right'caption='[[5ux4]], [[Resolution|resolution]] 2.81Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[5ux4]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UX4 OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[5ux4]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UX4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5UX4 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3UT:(5S)-3-(5,6-DIHYDRO-2H-PYRAN-3-YL)-1-FLUORO-7-(2-FLUOROPYRIDIN-3-YL)SPIRO[CHROMENO[2,3-C]PYRIDINE-5,4-[1,3]OXAZOL]-2-AMINE'>3UT</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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]] 2.805Å</td></tr> |
| - | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3UT:(5S)-3-(5,6-DIHYDRO-2H-PYRAN-3-YL)-1-FLUORO-7-(2-FLUOROPYRIDIN-3-YL)SPIRO[CHROMENO[2,3-C]PYRIDINE-5,4-[1,3]OXAZOL]-2-AMINE'>3UT</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5ux4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ux4 OCA], [https://pdbe.org/5ux4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ux4 RCSB], [https://www.ebi.ac.uk/pdbsum/5ux4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ux4 ProSAT]</span></td></tr> |
</table> | </table> | ||
== Function == | == Function == | ||
| - | [ | + | [https://www.uniprot.org/uniprot/CATD_RAT CATD_RAT] Acid protease active in intracellular protein breakdown. Plays a role in APP processing following cleavage and activation by ADAM30 which leads to APP degradation.[UniProtKB:P07339] |
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | As part of an ongoing effort at Amgen to develop a disease-modifying therapy for Alzheimer's disease, we have previously used the aminooxazoline xanthene (AOX) scaffold to generate potent and orally efficacious BACE1 inhibitors. While AOX-BACE1 inhibitors demonstrated acceptable cardiovascular safety margins, a retinal pathological finding in rat toxicological studies demanded further investigation. It has been widely postulated that such retinal toxicity might be related to off-target inhibition of Cathepsin D (CatD), a closely related aspartyl protease. We report the development of AOX-BACE1 inhibitors with improved selectivity against CatD by following a structure- and property-based approach. Our efforts culminated in the discovery of a picolinamide-substituted 3-aza-AOX-BACE1 inhibitor absent of retinal effects in an early screening rat toxicology study. | ||
| + | |||
| + | Development of 2-aminooxazoline 3-azaxanthene beta-amyloid cleaving enzyme (BACE) inhibitors with improved selectivity against Cathepsin D.,Low JD, Bartberger MD, Chen K, Cheng Y, Fielden MR, Gore V, Hickman D, Liu Q, Allen Sickmier E, Vargas HM, Werner J, White RD, Whittington DA, Wood S, Minatti AE Medchemcomm. 2017 Apr 27;8(6):1196-1206. doi: 10.1039/c7md00106a. eCollection, 2017 Jun 1. PMID:30108829<ref>PMID:30108829</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 5ux4" style="background-color:#fffaf0;"></div> | ||
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| + | ==See Also== | ||
| + | *[[Cathepsin 3D structures|Cathepsin 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| - | [[Category: | + | [[Category: Large Structures]] |
| - | [[Category: | + | [[Category: Rattus norvegicus]] |
| - | [[Category: | + | [[Category: Sickmier A]] |
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Current revision
Crystal Structure of Rat Cathepsin D with (5S)-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro- 7-(2-fluoropyridin-3-yl)spiro[chromeno[2,3- c]pyridine-5,4'-[1,3]oxazol]-2'-amine
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