3ixk

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[[Image:3ixk.png|left|200px]]
 
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{{STRUCTURE_3ixk| PDB=3ixk | SCENE= }}
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==Potent beta-secretase 1 inhibitor==
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<StructureSection load='3ixk' size='340' side='right'caption='[[3ixk]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3ixk]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3IXK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3IXK FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=929:N-[(1S,2S,4R)-5-{[(1S)-1-(benzylcarbamoyl)-2-methylpropyl]amino}-1-{[(3,5-difluorobenzyl)oxy]methyl}-2-hydroxy-4-methyl-5-oxopentyl]-5-[methyl(methylsulfonyl)amino]-N-[(1R)-1-phenylethyl]benzene-1,3-dicarboxamide+(non-preferred+name)'>929</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3ixk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ixk OCA], [https://pdbe.org/3ixk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ixk RCSB], [https://www.ebi.ac.uk/pdbsum/3ixk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ixk ProSAT]</span></td></tr>
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</table>
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== Function ==
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[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>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ix/3ixk_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=3ixk ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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We herein describe the design and synthesis of a series of BACE-1 inhibitors incorporating a P1-substituted hydroxylethylene transition state isostere. The synthetic route starting from commercially available carbohydrates yielded a pivotal lactone intermediate with excellent stereochemical control which subsequently could be diversified at the P1-position. The final inhibitors were optimized using three different amines to provide the residues in the P2'-P3' position and three different acids affording the residues in the P2-P3 position. In addition we report on the stereochemical preference of the P1'-methyl substituent in the synthesized inhibitors. All inhibitors were evaluated in an in vitro BACE-1 assay where the most potent inhibitor, 34-(R), exhibited a BACE-1 IC(50) value of 3.1 nM.
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===Potent beta-secretase 1 inhibitor===
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Synthesis of potent BACE-1 inhibitors incorporating a hydroxyethylene isostere as central core.,Wangsell F, Gustafsson K, Kvarnstrom I, Borkakoti N, Edlund M, Jansson K, Lindberg J, Hallberg A, Rosenquist A, Samuelsson B Eur J Med Chem. 2010 Mar;45(3):870-82. Epub 2009 Nov 12. PMID:20036448<ref>PMID:20036448</ref>
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{{ABSTRACT_PUBMED_20036448}}
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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==About this Structure==
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<div class="pdbe-citations 3ixk" style="background-color:#fffaf0;"></div>
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[[3ixk]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3IXK OCA].
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==See Also==
==See Also==
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*[[Beta secretase|Beta secretase]]
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*[[Beta secretase 3D structures|Beta secretase 3D structures]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:020036448</ref><references group="xtra"/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Memapsin 2]]
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[[Category: Large Structures]]
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[[Category: Borkakoti, N.]]
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[[Category: Borkakoti N]]
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[[Category: Lindberg, J D.]]
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[[Category: Lindberg JD]]
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[[Category: Nystrom, S.]]
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[[Category: Nystrom S]]
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[[Category: Aspartyl protease]]
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[[Category: Bace]]
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[[Category: Beta-secretase]]
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[[Category: Disulfide bond]]
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[[Category: Glycoprotein]]
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[[Category: Hydrolase]]
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[[Category: Inhibitor]]
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[[Category: Membrane]]
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[[Category: Protease]]
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[[Category: Statine]]
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[[Category: Transmembrane]]
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[[Category: Zymogen]]
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Current revision

Potent beta-secretase 1 inhibitor

PDB ID 3ixk

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