2wf3: Difference between revisions
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<StructureSection load='2wf3' size='340' side='right'caption='[[2wf3]], [[Resolution|resolution]] 2.08Å' scene=''> | <StructureSection load='2wf3' size='340' side='right'caption='[[2wf3]], [[Resolution|resolution]] 2.08Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2wf3]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[2wf3]] 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=2WF3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2WF3 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=ZY3:N-{(1S,2R)-1-BENZYL-2-HYDROXY-3-[(3-METHOXYBENZYL)AMINO]PROPYL}-6-(ETHYLAMINO)-1-METHYL-1,3,4,5-TETRAHYDRO-2,1-BENZOTHIAZEPINE-8-CARBOXAMIDE+2,2-DIOXIDE'>ZY3</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.08Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=ZY3:N-{(1S,2R)-1-BENZYL-2-HYDROXY-3-[(3-METHOXYBENZYL)AMINO]PROPYL}-6-(ETHYLAMINO)-1-METHYL-1,3,4,5-TETRAHYDRO-2,1-BENZOTHIAZEPINE-8-CARBOXAMIDE+2,2-DIOXIDE'>ZY3</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=2wf3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wf3 OCA], [https://pdbe.org/2wf3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2wf3 RCSB], [https://www.ebi.ac.uk/pdbsum/2wf3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2wf3 ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == 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 == | == Evolutionary Conservation == | ||
[[Image:Consurf_key_small.gif|200px|right]] | [[Image:Consurf_key_small.gif|200px|right]] | ||
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<jmolCheckbox> | <jmolCheckbox> | ||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/wf/2wf3_consurf.spt"</scriptWhenChecked> | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/wf/2wf3_consurf.spt"</scriptWhenChecked> | ||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/ | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> | ||
<text>to colour the structure by Evolutionary Conservation</text> | <text>to colour the structure by Evolutionary Conservation</text> | ||
</jmolCheckbox> | </jmolCheckbox> | ||
| Line 37: | Line 36: | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Charrier N]] | |||
[[Category: Clarke B]] | |||
[[Category: Charrier | [[Category: Demont E]] | ||
[[Category: Clarke | [[Category: Dingwall C]] | ||
[[Category: Demont | [[Category: Dunsdon R]] | ||
[[Category: Dingwall | [[Category: Hawkins J]] | ||
[[Category: Dunsdon | [[Category: Hubbard J]] | ||
[[Category: Hawkins | [[Category: Hussain I]] | ||
[[Category: Hubbard | [[Category: Maile G]] | ||
[[Category: Hussain | [[Category: Matico R]] | ||
[[Category: Maile | [[Category: Mosley J]] | ||
[[Category: Matico | [[Category: Naylor A]] | ||
[[Category: Mosley | [[Category: O'Brien A]] | ||
[[Category: Naylor | [[Category: Redshaw S]] | ||
[[Category: Redshaw | [[Category: Rowland P]] | ||
[[Category: Rowland | [[Category: Smith KJ]] | ||
[[Category: Smith | [[Category: Soleil V]] | ||
[[Category: Soleil | [[Category: Sweitzer S]] | ||
[[Category: Sweitzer | [[Category: Theobald P]] | ||
[[Category: Theobald | [[Category: Vesey D]] | ||
[[Category: Vesey | [[Category: Walter DS]] | ||
[[Category: Walter | [[Category: Wayne G]] | ||
[[Category: Wayne | |||
Latest revision as of 11:02, 23 October 2024
Human BACE-1 in complex with 6-(ethylamino)-N-((1S,2R)-2-hydroxy-3-(((3-(methyloxy)phenyl)methyl)amino)-1-(phenylmethyl)propyl)-1-methyl-1, 3,4,5-tetrahydro-2,1-benzothiazepine-8-carboxamide 2,2-dioxideHuman BACE-1 in complex with 6-(ethylamino)-N-((1S,2R)-2-hydroxy-3-(((3-(methyloxy)phenyl)methyl)amino)-1-(phenylmethyl)propyl)-1-methyl-1, 3,4,5-tetrahydro-2,1-benzothiazepine-8-carboxamide 2,2-dioxide
Structural highlights
FunctionBACE1_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.[1] [2] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedOur first generation of hydroxyethylamine transition-state mimetic BACE-1 inhibitors allowed us to validate BACE-1 as a key target for Alzheimer's disease by demonstrating amyloid lowering in an animal model, albeit at rather high doses. Finding a molecule from this series which was active at lower oral doses proved elusive and demonstrated the need to find a novel series of inhibitors with improved pharmacokinetics. This Letter describes the discovery of such inhibitors. Second generation of BACE-1 inhibitors part 2: Optimisation of the non-prime side substituent.,Charrier N, Clarke B, Demont E, Dingwall C, Dunsdon R, Hawkins J, Hubbard J, Hussain I, Maile G, Matico R, Mosley J, Naylor A, O'Brien A, Redshaw S, Rowland P, Soleil V, Smith KJ, Sweitzer S, Theobald P, Vesey D, Walter DS, Wayne G Bioorg Med Chem Lett. 2009 Jul 1;19(13):3669-73. Epub 2009 Apr 5. PMID:19477642[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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