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[[Image:2is0.gif|left|200px]]
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{{STRUCTURE_2is0|  PDB=2is0  |  SCENE=  }}
'''Crystal structure of human Beta-secretase complexed with inhibitor'''


==Crystal structure of human Beta-secretase complexed with inhibitor==
<StructureSection load='2is0' size='340' side='right'caption='[[2is0]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2is0]] 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=2IS0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2IS0 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=I03:(2S)-2-AMINO-2-BENZYL-3-HYDROXYPROPYL+3-({[(1R)-1-(4-FLUOROPHENYL)ETHYL]AMINO}CARBONYL)-5-[METHYL(METHYLSULFONYL)AMINO]BENZOATE'>I03</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=2is0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2is0 OCA], [https://pdbe.org/2is0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2is0 RCSB], [https://www.ebi.ac.uk/pdbsum/2is0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2is0 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/is/2is0_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=2is0 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
We describe the discovery and optimization of tertiary carbinamine derived inhibitors of the enzyme beta-secretase (BACE-1). These novel non-transition-state-derived ligands incorporate a single primary amine to interact with the catalytic aspartates of the target enzyme. Optimization of this series provided inhibitors with intrinsic and functional potency comparable to evolved transition state isostere derived inhibitors of BACE-1.


==Overview==
Discovery of oxadiazoyl tertiary carbinamine inhibitors of beta-secretase (BACE-1).,Rajapakse HA, Nantermet PG, Selnick HG, Munshi S, McGaughey GB, Lindsley SR, Young MB, Lai MT, Espeseth AS, Shi XP, Colussi D, Pietrak B, Crouthamel MC, Tugusheva K, Huang Q, Xu M, Simon AJ, Kuo L, Hazuda DJ, Graham S, Vacca JP J Med Chem. 2006 Dec 14;49(25):7270-3. PMID:17149856<ref>PMID:17149856</ref>
We describe the discovery and optimization of tertiary carbinamine derived inhibitors of the enzyme beta-secretase (BACE-1). These novel non-transition-state-derived ligands incorporate a single primary amine to interact with the catalytic aspartates of the target enzyme. Optimization of this series provided inhibitors with intrinsic and functional potency comparable to evolved transition state isostere derived inhibitors of BACE-1.


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
2IS0 is a [[Single protein]] 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=2IS0 OCA].
</div>
<div class="pdbe-citations 2is0" style="background-color:#fffaf0;"></div>


==Reference==
==See Also==
Discovery of oxadiazoyl tertiary carbinamine inhibitors of beta-secretase (BACE-1)., Rajapakse HA, Nantermet PG, Selnick HG, Munshi S, McGaughey GB, Lindsley SR, Young MB, Lai MT, Espeseth AS, Shi XP, Colussi D, Pietrak B, Crouthamel MC, Tugusheva K, Huang Q, Xu M, Simon AJ, Kuo L, Hazuda DJ, Graham S, Vacca JP, J Med Chem. 2006 Dec 14;49(25):7270-3. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17149856 17149856]
*[[Beta secretase 3D structures|Beta secretase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Memapsin 2]]
[[Category: Large Structures]]
[[Category: Single protein]]
[[Category: Munshi S]]
[[Category: Munshi, S.]]
[[Category: Aspartyl protease]]
[[Category: Hydrolase]]
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May  4 07:47:50 2008''

Latest revision as of 09:12, 6 November 2024

Crystal structure of human Beta-secretase complexed with inhibitor

2is0, resolution 2.20Å

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