View source for 2va7


==X-ray crystal structure of beta secretase complexed with compound 27==
<StructureSection load='2va7' size='340' side='right'caption='[[2va7]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2va7]] 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=2VA7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VA7 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C27:(6R)-2-AMINO-6-[2-(3-METHOXYBIPHENYL-3-YL)ETHYL]-3,6-DIMETHYL-5,6-DIHYDROPYRIMIDIN-4(3H)-ONE'>C27</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></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=2va7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2va7 OCA], [https://pdbe.org/2va7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2va7 RCSB], [https://www.ebi.ac.uk/pdbsum/2va7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2va7 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/va/2va7_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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=2va7 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.

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>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2va7" style="background-color:#fffaf0;"></div>

==See Also==
*[[Beta secretase 3D structures|Beta secretase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Aharony D]]
[[Category: Albert JS]]
[[Category: Andisik D]]
[[Category: Callaghan O]]
[[Category: Campbell JB]]
[[Category: Carr RA]]
[[Category: Chessari G]]
[[Category: Congreve M]]
[[Category: Edwards PD]]
[[Category: Folmer RHA]]
[[Category: Frederickson M]]
[[Category: Geschwindner S]]
[[Category: Koether G]]
[[Category: Kolmodin K]]
[[Category: Krumrine J]]
[[Category: Mauger RC]]
[[Category: Murray CW]]
[[Category: Olsson LL]]
[[Category: Patel S]]
[[Category: Spear N]]
[[Category: Sylvester M]]
[[Category: Tian G]]