2vij: Difference between revisions
New page: left|200px<br /><applet load="2vij" size="350" color="white" frame="true" align="right" spinBox="true" caption="2vij, resolution 1.60Å" /> '''HUMAN BACE-1 IN COMP... |
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== | ==Human BACE-1 in complex with 3-(1,1-dioxidotetrahydro-2H-1,2-thiazin- 2-yl)-5-(ethylamino)-N-((1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(1,2,3,4- tetrahydro-1-naphthalenylamino)propyl)benzamide== | ||
This article is focusing on further optimization of previously described | <StructureSection load='2vij' size='340' side='right'caption='[[2vij]], [[Resolution|resolution]] 1.60Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2vij]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VIJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VIJ FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C44:N-{(1S,2R)-1-BENZYL-2-HYDROXY-3-[(1S)-1,2,3,4-TETRAHYDRONAPHTHALEN-1-YLAMINO]PROPYL}-3-(1,1-DIOXIDO-1,2-THIAZINAN-2-YL)-5-(ETHYLAMINO)BENZAMIDE'>C44</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1m4h|1m4h]], [[1sgz|1sgz]], [[1w50|1w50]], [[1w51|1w51]], [[1xs7|1xs7]], [[1ym4|1ym4]], [[1fkn|1fkn]], [[1py1|1py1]], [[1tqf|1tqf]], [[1ujj|1ujj]], [[1ujk|1ujk]], [[1xn2|1xn2]], [[1xn3|1xn3]], [[1ym2|1ym2]], [[2b8l|2b8l]], [[2b8v|2b8v]], [[2va5|2va5]], [[2va6|2va6]], [[2va7|2va7]], [[2vie|2vie]]</div></td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=2vij FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vij OCA], [https://pdbe.org/2vij PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2vij RCSB], [https://www.ebi.ac.uk/pdbsum/2vij PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2vij 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/vi/2vij_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=2vij ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
This article is focusing on further optimization of previously described hydroxy ethylamine (HEA) BACE-1 inhibitors obtained from a focused library with the support of X-ray crystallography. Optimization of the non-prime side of our inhibitors and introduction of a 6-membered sultam substituent binding to Asn-294 as well as a fluorine in the C-2 position led to derivatives with nanomolar potency in cell-based assays. | |||
BACE-1 inhibitors part 3: identification of hydroxy ethylamines (HEAs) with nanomolar potency in cells.,Beswick P, Charrier N, Clarke B, Demont E, Dingwall C, Dunsdon R, Faller A, Gleave R, Hawkins J, Hussain I, Johnson CN, MacPherson D, Maile G, Matico R, Milner P, Mosley J, Naylor A, O'Brien A, Redshaw S, Riddell D, Rowland P, Skidmore J, Soleil V, Smith KJ, Stanway S, Stemp G, Stuart A, Sweitzer S, Theobald P, Vesey D, Walter DS, Ward J, Wayne G Bioorg Med Chem Lett. 2008 Feb 1;18(3):1022-6. Epub 2007 Dec 15. PMID:18171615<ref>PMID:18171615</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
[[Category: | <div class="pdbe-citations 2vij" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Beta secretase 3D structures|Beta secretase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Memapsin 2]] | [[Category: Memapsin 2]] | ||
[[Category: Beswick, P]] | |||
[[Category: Beswick, P | [[Category: Brien, A O]] | ||
[[Category: Brien, A | [[Category: Charrier, N]] | ||
[[Category: Charrier, N | [[Category: Clarke, B]] | ||
[[Category: Clarke, B | [[Category: Demont, E]] | ||
[[Category: Demont, E | [[Category: Dingwall, C]] | ||
[[Category: Dingwall, C | [[Category: Dunsdon, R]] | ||
[[Category: Dunsdon, R | [[Category: Faller, A]] | ||
[[Category: Faller, A | [[Category: Gleave, R]] | ||
[[Category: Gleave, R | [[Category: Hawkins, J]] | ||
[[Category: Hawkins, J | [[Category: Hussain, I]] | ||
[[Category: Hussain, I | [[Category: Johnson, C N]] | ||
[[Category: Johnson, C | [[Category: Macpherson, D]] | ||
[[Category: Macpherson, D | [[Category: Maile, G]] | ||
[[Category: Maile, G | [[Category: Matico, R]] | ||
[[Category: Matico, R | [[Category: Milner, P]] | ||
[[Category: Milner, P | [[Category: Mosley, J]] | ||
[[Category: Mosley, J | [[Category: Naylor, A]] | ||
[[Category: Naylor, A | [[Category: Redshaw, S]] | ||
[[Category: Redshaw, S | [[Category: Riddell, D]] | ||
[[Category: Riddell, D | [[Category: Rowland, P]] | ||
[[Category: Rowland, P | [[Category: Skidmore, J]] | ||
[[Category: Skidmore, J | [[Category: Smith, K J]] | ||
[[Category: Smith, K | [[Category: Soleil, V]] | ||
[[Category: Soleil, V | [[Category: Stanway, S]] | ||
[[Category: Stanway, S | [[Category: Stemp, G]] | ||
[[Category: Stemp, G | [[Category: Stuart, A]] | ||
[[Category: Stuart, A | [[Category: Sweitzer, S]] | ||
[[Category: Sweitzer, S | [[Category: Theobald, P]] | ||
[[Category: Theobald, P | [[Category: Vesey, D]] | ||
[[Category: Vesey, D | [[Category: Walter, D S]] | ||
[[Category: Walter, D | [[Category: Ward, J]] | ||
[[Category: Ward, J | [[Category: Wayne, G]] | ||
[[Category: Wayne, G | [[Category: Alternative splicing]] | ||
[[Category: Asp-2]] | |||
[[Category: | [[Category: Aspartyl protease]] | ||
[[Category: | [[Category: Bace-1]] | ||
[[Category: | [[Category: Beta-secretase]] | ||
[[Category: | [[Category: Beta-site app cleaving enzyme]] | ||
[[Category: | [[Category: Glycoprotein]] | ||
[[Category: | [[Category: Hydrolase]] | ||
[[Category: | [[Category: Memapsin-2]] | ||
[[Category: | [[Category: Membrane]] | ||
[[Category: | [[Category: Protease]] | ||
[[Category: | [[Category: Transmembrane]] | ||
[[Category: | [[Category: Zymogen]] | ||
[[Category: | |||
[[Category: | |||
