3udr: Difference between revisions
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==Crystal Structure of BACE with Compound 14== | ==Crystal Structure of BACE with Compound 14== | ||
<StructureSection load='3udr' size='340' side='right' caption='[[3udr]], [[Resolution|resolution]] 1.95Å' scene=''> | <StructureSection load='3udr' size='340' side='right' caption='[[3udr]], [[Resolution|resolution]] 1.95Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3udr]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[3udr]] is a 1 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=3UDR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3UDR FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=09F:1-CYANOCYCLOHEXYL+(3S,5R)-2-OXO-1,2-DIHYDROSPIRO[INDOLE-3,3-PYRROLIDINE]-5-CARBOXYLATE'>09F</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=09F:1-CYANOCYCLOHEXYL+(3S,5R)-2-OXO-1,2-DIHYDROSPIRO[INDOLE-3,3-PYRROLIDINE]-5-CARBOXYLATE'>09F</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3udh|3udh]], [[3udj|3udj]], [[3udk|3udk]], [[3udm|3udm]], [[3udn|3udn]], [[3udp|3udp]], [[3udq|3udq]], [[3udy|3udy]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3udh|3udh]], [[3udj|3udj]], [[3udk|3udk]], [[3udm|3udm]], [[3udn|3udn]], [[3udp|3udp]], [[3udq|3udq]], [[3udy|3udy]]</td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE1, BACE, 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">BACE1, BACE, 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=3udr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3udr OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3udr RCSB], [http://www.ebi.ac.uk/pdbsum/3udr 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=3udr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3udr OCA], [http://pdbe.org/3udr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3udr RCSB], [http://www.ebi.ac.uk/pdbsum/3udr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3udr ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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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 3udr" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Human]] | ||
[[Category: Memapsin 2]] | [[Category: Memapsin 2]] | ||
[[Category: Borzilleri, K]] | [[Category: Borzilleri, K]] | ||
Revision as of 15:18, 5 August 2016
Crystal Structure of BACE with Compound 14Crystal Structure of BACE with Compound 14
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 PubMedThe aspartyl protease beta-secretase, or BACE1, has been demonstrated to be a key factor in the proteolytic formation of Abeta-peptide, a major component of plaques in the brains of Alzheimer's Disease (AD) patients, and inhibition of this enzyme has emerged as a major strategy for pharmacologic intervention in AD. An X-ray based fragment screen of Pfizer's proprietary fragment collection has resulted in the identification of a novel BACE binder featuring spiropyrrolidine framework. Although exhibiting only weak inhibitory activity against the BACE enzyme, the small compound was verified by biophysical and NMR-based methods as a bona fide BACE inhibitor. Subsequent optimization of the lead compound, relying heavily on structure-based drug design and computational prediction of physiochemical properties, resulted in a 1000-fold improvement in potency while maintaining ligand efficiency and properties predictive of good permeability and low P-gp liability. Discovery and Optimization of a Novel Spiro-pyrrolidine Inhibitors of beta-Secretase (BACE1) Through Fragment Based Drug Design.,Efremov IV, Vajdos FF, Borzilleri K, Capetta S, Dorff PH, Dutra JK, Mansour M, Chen H, Goldstein SW, Noell S, Oborski CE, O'Connell TN, O'Sullivan TJ, Pandit J, Wang H, Wei B, Withka JM, McColl A J Med Chem. 2012 Apr 2. PMID:22468999[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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