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3k5d
From Proteopedia
(Difference between revisions)
(New page: '''Unreleased structure''' The entry 3k5d is ON HOLD Authors: Rondeau, J.-M. Description: Crystal Structure of BACE-1 in complex with AHM178 ''Page seeded by [http://oca.weizmann.ac.i...) |
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal Structure of BACE-1 in complex with AHM178== | |
| + | <StructureSection load='3k5d' size='340' side='right' caption='[[3k5d]], [[Resolution|resolution]] 2.90Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[3k5d]] is a 3 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=3K5D OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3K5D FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=XLI:N-ACETYL-L-LEUCYL-N-[(4S,5S,7R)-8-(BUTYLAMINO)-5-HYDROXY-2,7-DIMETHYL-8-OXOOCTAN-4-YL]-L-METHIONINAMIDE'>XLI</scene></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 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='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=3k5d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3k5d OCA], [http://pdbe.org/3k5d PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3k5d RCSB], [http://www.ebi.ac.uk/pdbsum/3k5d PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3k5d ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://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/k5/3k5d_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=3k5d ConSurf]. | ||
| + | <div style="clear:both"></div> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Starting from peptidomimetic BACE-1 inhibitors, the P2 amino acid including the P2/P3 peptide bond was replaced by a rigid 3-aminomethyl cyclohexane carboxylic acid. Co-crystallization revealed an unexpected binding mode with the P3/P4 amide bond placed into the S3 pocket resulting in a new hydrogen bond interaction pattern. Further optimization based on this structure resulted in highly potent BACE-1 inhibitors with selectivity over BACE-2 and cathepsin D. | ||
| - | + | Structure-based design and synthesis of novel P2/P3 modified, non-peptidic beta-secretase (BACE-1) inhibitors.,Hanessian S, Shao Z, Betschart C, Rondeau JM, Neumann U, Tintelnot-Blomley M Bioorg Med Chem Lett. 2010 Mar 15;20(6):1924-7. Epub 2010 Feb 2. PMID:20172717<ref>PMID:20172717</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | <div class="pdbe-citations 3k5d" style="background-color:#fffaf0;"></div> | |
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Human]] | ||
| + | [[Category: Memapsin 2]] | ||
| + | [[Category: Rondeau, J M]] | ||
| + | [[Category: Alzheimer's disease]] | ||
| + | [[Category: Aspartyl protease]] | ||
| + | [[Category: Endoplasmic reticulum]] | ||
| + | [[Category: Endosome]] | ||
| + | [[Category: Glycoprotein]] | ||
| + | [[Category: Golgi apparatus]] | ||
| + | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
| + | [[Category: Membrane]] | ||
| + | [[Category: Protease]] | ||
| + | [[Category: Transmembrane]] | ||
Current revision
Crystal Structure of BACE-1 in complex with AHM178
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