2va5

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{{Seed}}
 
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[[Image:2va5.png|left|200px]]
 
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==X-ray crystal structure of beta secretase complexed with compound 8c==
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The line below this paragraph, containing "STRUCTURE_2va5", creates the "Structure Box" on the page.
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<StructureSection load='2va5' size='340' side='right'caption='[[2va5]], [[Resolution|resolution]] 2.75&Aring;' scene=''>
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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== Structural highlights ==
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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<table><tr><td colspan='2'>[[2va5]] is a 1 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=2VA5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VA5 FirstGlance]. <br>
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or leave the SCENE parameter empty for the default display.
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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]] 2.75&#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=C8C:2-AMINO-6-[2-(1H-INDOL-6-YL)ETHYL]PYRIMIDIN-4(3H)-ONE'>C8C</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr>
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{{STRUCTURE_2va5| PDB=2va5 | SCENE= }}
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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=2va5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2va5 OCA], [https://pdbe.org/2va5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2va5 RCSB], [https://www.ebi.ac.uk/pdbsum/2va5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2va5 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/va/2va5_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=2va5 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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Fragment-based lead generation has led to the discovery of a novel series of cyclic amidine-based inhibitors of beta-secretase (BACE-1). Initial fragment hits with an isocytosine core having millimolar potency were identified via NMR affinity screening. Structure-guided evolution of these fragments using X-ray crystallography together with potency determination using surface plasmon resonance and functional enzyme inhibition assays afforded micromolar inhibitors. Similarity searching around the isocytosine core led to the identification of a related series of inhibitors, the dihydroisocytosines. By leveraging the knowledge of the ligand-BACE-1 recognition features generated from the isocytosines, the dihydroisocytosines were efficiently optimized to submicromolar potency. Compound 29, with an IC50 of 80 nM, a ligand efficiency of 0.37, and cellular activity of 470 nM, emerged as the lead structure for future optimization.
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===X-RAY CRYSTAL STRUCTURE OF BETA SECRETASE COMPLEXED WITH COMPOUND 8C===
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Application of fragment-based lead generation to the discovery of novel, cyclic amidine beta-secretase inhibitors with nanomolar potency, cellular activity, and high ligand efficiency.,Edwards PD, Albert JS, Sylvester M, Aharony D, Andisik D, Callaghan O, Campbell JB, Carr RA, Chessari G, Congreve M, Frederickson M, Folmer RH, Geschwindner S, Koether G, Kolmodin K, Krumrine J, Mauger RC, Murray CW, Olsson LL, Patel S, Spear N, Tian G J Med Chem. 2007 Nov 29;50(24):5912-25. Epub 2007 Nov 7. PMID:17985862<ref>PMID:17985862</ref>
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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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<div class="pdbe-citations 2va5" style="background-color:#fffaf0;"></div>
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==See Also==
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The line below this paragraph, {{ABSTRACT_PUBMED_17985862}}, adds the Publication Abstract to the page
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*[[Beta secretase 3D structures|Beta secretase 3D structures]]
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(as it appears on PubMed at http://www.pubmed.gov), where 17985862 is the PubMed ID number.
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== References ==
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<references/>
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{{ABSTRACT_PUBMED_17985862}}
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__TOC__
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</StructureSection>
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==About this Structure==
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2VA5 is a 1 chain structure of 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=2VA5 OCA].
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==Reference==
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<ref group="xtra">PMID:17985862</ref><references group="xtra"/>
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[[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: Aharony, D.]]
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[[Category: Aharony D]]
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[[Category: Albert, J S.]]
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[[Category: Albert JS]]
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[[Category: Andisik, D.]]
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[[Category: Andisik D]]
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[[Category: Callaghan, O.]]
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[[Category: Callaghan O]]
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[[Category: Campbell, J B.]]
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[[Category: Campbell JB]]
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[[Category: Carr, R A.]]
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[[Category: Carr RA]]
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[[Category: Chessari, G.]]
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[[Category: Chessari G]]
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[[Category: Congreve, M.]]
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[[Category: Congreve M]]
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[[Category: Edwards, P D.]]
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[[Category: Edwards PD]]
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[[Category: Folmer, R H.A.]]
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[[Category: Folmer RHA]]
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[[Category: Frederickson, M.]]
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[[Category: Frederickson M]]
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[[Category: Geschwindner, S.]]
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[[Category: Geschwindner S]]
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[[Category: Koether, G.]]
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[[Category: Koether G]]
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[[Category: Kolmodin, K.]]
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[[Category: Kolmodin K]]
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[[Category: Krumrine, J.]]
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[[Category: Krumrine J]]
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[[Category: Mauger, R C.]]
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[[Category: Mauger RC]]
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[[Category: Murray, C W.]]
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[[Category: Murray CW]]
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[[Category: Olsson, L.]]
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[[Category: Olsson L]]
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[[Category: Patel, S.]]
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[[Category: Patel S]]
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[[Category: Spear, N.]]
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[[Category: Spear N]]
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[[Category: Sylvester, M.]]
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[[Category: Sylvester M]]
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[[Category: Tian, G.]]
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[[Category: Tian G]]
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[[Category: Alternative splicing]]
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[[Category: Alzheimer's disease]]
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[[Category: Aspartic protease]]
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[[Category: Aspartyl protease]]
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[[Category: Base]]
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[[Category: Beta-secretase]]
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[[Category: Glycoprotein]]
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[[Category: Hydrolase]]
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[[Category: Memapsin 2]]
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[[Category: Membrane]]
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[[Category: Protease]]
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[[Category: Transmembrane]]
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[[Category: Zymogen]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Feb 17 05:26:10 2009''
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Current revision

X-ray crystal structure of beta secretase complexed with compound 8c

PDB ID 2va5

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