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==Crystal structure of beta-site app-cleaving enzyme 1 (bace-wt) complex with bms-681889 aka n~1~-butyl-5-cyano- n~3~-((1s,2r)-1-(3,5-difluorobenzyl)-2-hydroxy-3-((3- methoxybenzyl)amino)propyl)-n~1~-methyl-1h-indole-1,3- dicarboxamide== | ==Crystal structure of beta-site app-cleaving enzyme 1 (bace-wt) complex with bms-681889 aka n~1~-butyl-5-cyano- n~3~-((1s,2r)-1-(3,5-difluorobenzyl)-2-hydroxy-3-((3- methoxybenzyl)amino)propyl)-n~1~-methyl-1h-indole-1,3- dicarboxamide== | ||
<StructureSection load='3ohh' size='340' side='right' caption='[[3ohh]], [[Resolution|resolution]] 2.01Å' scene=''> | <StructureSection load='3ohh' size='340' side='right' caption='[[3ohh]], [[Resolution|resolution]] 2.01Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3ohh]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[3ohh]] 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=3OHH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3OHH FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3HH:N~1~-BUTYL-5-CYANO-N~3~-{(1S,2R)-1-(3,5-DIFLUOROBENZYL)-2-HYDROXY-3-[(3-METHOXYBENZYL)AMINO]PROPYL}-N~1~-METHYL-1H-INDOLE-1,3-DICARBOXAMIDE'>3HH</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3HH:N~1~-BUTYL-5-CYANO-N~3~-{(1S,2R)-1-(3,5-DIFLUOROBENZYL)-2-HYDROXY-3-[(3-METHOXYBENZYL)AMINO]PROPYL}-N~1~-METHYL-1H-INDOLE-1,3-DICARBOXAMIDE'>3HH</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3ohf|3ohf]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3ohf|3ohf]]</td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE, BACE1, KIAA1149 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE, BACE1, 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=3ohh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ohh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3ohh RCSB], [http://www.ebi.ac.uk/pdbsum/3ohh PDBsum]</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=3ohh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ohh OCA], [http://pdbe.org/3ohh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3ohh RCSB], [http://www.ebi.ac.uk/pdbsum/3ohh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3ohh ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
| Line 19: | Line 20: | ||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 3ohh" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
| Line 26: | Line 28: | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Human]] | ||
[[Category: Memapsin 2]] | [[Category: Memapsin 2]] | ||
[[Category: Muckelbauer, J K]] | [[Category: Muckelbauer, J K]] | ||
Revision as of 21:36, 5 August 2016
Crystal structure of beta-site app-cleaving enzyme 1 (bace-wt) complex with bms-681889 aka n~1~-butyl-5-cyano- n~3~-((1s,2r)-1-(3,5-difluorobenzyl)-2-hydroxy-3-((3- methoxybenzyl)amino)propyl)-n~1~-methyl-1h-indole-1,3- dicarboxamideCrystal structure of beta-site app-cleaving enzyme 1 (bace-wt) complex with bms-681889 aka n~1~-butyl-5-cyano- n~3~-((1s,2r)-1-(3,5-difluorobenzyl)-2-hydroxy-3-((3- methoxybenzyl)amino)propyl)-n~1~-methyl-1h-indole-1,3- dicarboxamide
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 PubMedHeterocyclic replacement of the isophthalamide phenyl ring in hydroxyethylamine (HEA) BACE-1 inhibitors was explored. A variety of indole-1,3-dicarboxamide HEAs exhibited potent BACE-1 enzyme inhibition, but displayed poor cellular activity. Improvements in cellular activity and aspartic protease selectivity were observed for 7-azaindole-1,3-dicarboxamide HEAs. A methylprolinol-bearing derivative (10n) demonstrated robust reductions in rat plasma Abeta levels, but did not lower rat brain Abeta due to poor central exposure. The same analog exhibited a high efflux ratio in a bidirectional Caco-2 assay and was likely a substrate of the efflux transporter P-glycoprotein. X-ray crystal structures are reported for two indole HEAs in complex with BACE-1. Synthesis and SAR of indole-and 7-azaindole-1,3-dicarboxamide hydroxyethylamine inhibitors of BACE-1.,Marcin LR, Higgins MA, Zusi FC, Zhang Y, Dee MF, Parker MF, Muckelbauer JK, Camac DM, Morin PE, Ramamurthy V, Tebben AJ, Lentz KA, Grace JE, Marcinkeviciene JA, Kopcho LM, Burton CR, Barten DM, Toyn JH, Meredith JE, Albright CF, Bronson JJ, Macor JE, Thompson LA Bioorg Med Chem Lett. 2011 Jan 1;21(1):537-41. PMID:21078556[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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