2f3e
From Proteopedia
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| - | [[Image:2f3e.png|left|200px]] | ||
| - | { | + | ==Crystal Structure of the Bace complex with AXQ093, a macrocyclic inhibitor== |
| + | <StructureSection load='2f3e' size='340' side='right'caption='[[2f3e]], [[Resolution|resolution]] 2.11Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[2f3e]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2F3E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2F3E FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AXQ:{(E)-(3R,6S,9R)-3-[(1S,3R)-3-((S)-1+-BUTYLCARBAMOYL-2-METHYL-PROPYLCARB+AMOYL)-1-HYDROXY-BUTYL]-6-METHYL-5,+8-DIOXO-1,11-DITHIA-4,7-DIAZA-CYCLO+PENTADEC-13-EN-9-YL}-CARBAMIC+ACID+TERT-BUTYL+ESTER'>AXQ</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2f3f|2f3f]]</div></td></tr> | ||
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE1, BACE ([https://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'>[https://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=2f3e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2f3e OCA], [https://pdbe.org/2f3e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2f3e RCSB], [https://www.ebi.ac.uk/pdbsum/2f3e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2f3e 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> | ||
| + | == Evolutionary Conservation == | ||
| + | [[Image:Consurf_key_small.gif|200px|right]] | ||
| + | Check<jmol> | ||
| + | <jmolCheckbox> | ||
| + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/f3/2f3e_consurf.spt"</scriptWhenChecked> | ||
| + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | ||
| + | <text>to colour the structure by Evolutionary Conservation</text> | ||
| + | </jmolCheckbox> | ||
| + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2f3e ConSurf]. | ||
| + | <div style="clear:both"></div> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Based on the X-ray cocrystal structure of the Tang-Ghosh heptapeptide inhibitor 1 (OM00-3), a series of macroheterocyclic analogues were designed and synthesized. Analogues containing dithia, dioxa, oxathia, and carbathia macrocycles were synthesized by methods relying on ring-closing olefin metathesis for the dioxa analogues and by alkylation of thiolates or bisthiolates for the others. Molecular modeling suggested that the incorporation of piperidine units appended to the macrocycles improved interactions through additional H-bonds and introduced further rigidity. These were synthesized in enantiomerically pure form using enzyme-catalyzed desymmetrization and diastereomer separation. Inhibitory activity on beta-site amyloid precursor protein cleaving enzyme (BACE) was observed with several macroheterocyclic inhibitors and structure-activity relationship (SAR) correlations were deduced. Cocrystal structures of two synthetic analogues revealed interesting and unexpected binding interactions. | ||
| - | + | Structure-based design and synthesis of macroheterocyclic peptidomimetic inhibitors of the aspartic protease beta-site amyloid precursor protein cleaving enzyme (BACE).,Hanessian S, Yang G, Rondeau JM, Neumann U, Betschart C, Tintelnot-Blomley M J Med Chem. 2006 Jul 27;49(15):4544-67. PMID:16854060<ref>PMID:16854060</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | <div class="pdbe-citations 2f3e" style="background-color:#fffaf0;"></div> | |
| - | + | ||
==See Also== | ==See Also== | ||
| - | *[[Beta secretase|Beta secretase]] | + | *[[Beta secretase 3D structures|Beta secretase 3D structures]] |
| - | + | == References == | |
| - | == | + | <references/> |
| - | < | + | __TOC__ |
| - | [[Category: | + | </StructureSection> |
| + | [[Category: Human]] | ||
| + | [[Category: Large Structures]] | ||
[[Category: Memapsin 2]] | [[Category: Memapsin 2]] | ||
| - | [[Category: Rondeau, J M | + | [[Category: Rondeau, J M]] |
[[Category: Alzheimer's disease]] | [[Category: Alzheimer's disease]] | ||
[[Category: Aspartic protease]] | [[Category: Aspartic protease]] | ||
Current revision
Crystal Structure of the Bace complex with AXQ093, a macrocyclic inhibitor
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