3in4: Difference between revisions
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==Bace1 with Compound 38== | ==Bace1 with Compound 38== | ||
<StructureSection load='3in4' size='340' side='right' caption='[[3in4]], [[Resolution|resolution]] 2.30Å' scene=''> | <StructureSection load='3in4' size='340' side='right' caption='[[3in4]], [[Resolution|resolution]] 2.30Å' scene=''> | ||
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE1, BACE, KIAA1149 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE1, BACE, KIAA1149 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [http://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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3in4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3in4 OCA], [http://pdbe.org/3in4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3in4 RCSB], [http://www.ebi.ac.uk/pdbsum/3in4 PDBsum]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3in4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3in4 OCA], [http://pdbe.org/3in4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3in4 RCSB], [http://www.ebi.ac.uk/pdbsum/3in4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3in4 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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Check<jmol> | Check<jmol> | ||
<jmolCheckbox> | <jmolCheckbox> | ||
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/in/3in4_consurf.spt"</scriptWhenChecked> | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/in/3in4_consurf.spt"</scriptWhenChecked> | ||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | ||
<text>to colour the structure by Evolutionary Conservation</text> | <text>to colour the structure by Evolutionary Conservation</text> | ||
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[[Category: Memapsin 2]] | [[Category: Memapsin 2]] | ||
[[Category: Olland, A M]] | [[Category: Olland, A M]] | ||
[[Category: Alternative splicing]] | |||
[[Category: Aspartyl protease]] | [[Category: Aspartyl protease]] | ||
[[Category: Bace-1]] | [[Category: Bace-1]] | ||
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[[Category: Inhibitor]] | [[Category: Inhibitor]] | ||
[[Category: Membrane]] | [[Category: Membrane]] | ||
[[Category: Polymorphism]] | |||
[[Category: Protease]] | [[Category: Protease]] | ||
[[Category: Transmembrane]] | [[Category: Transmembrane]] | ||
[[Category: Zymogen]] | [[Category: Zymogen]] | ||
Revision as of 12:49, 19 December 2018
Bace1 with Compound 38Bace1 with Compound 38
Structural highlights
Function[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.[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 PubMedThe identification of highly selective small molecule di-substituted pyridinyl aminohydantoins as beta-secretase inhibitors is reported. The more potent and selective analogs demonstrate low nanomolar potency for the BACE1 enzyme as measured in a FRET assay, and exhibit comparable activity in a cell-based (ELISA) assay. In addition, these pyridine-aminohydantoins are highly selectivity (>500x) against the other structurally related aspartyl proteases BACE2, cathepsin D, pepsin and renin. Our design strategy followed a traditional SAR approach and was supported by molecular modeling studies based on the previously reported aminohydantoin 3a. We have taken advantage of the amino acid difference between the BACE1 and BACE2 at the S2' pocket (BACE1 Pro(70) changed to BACE2 Lys(86)) to build ligands with >500-fold selectivity against BACE2. The addition of large substituents on the targeted ligand at the vicinity of this aberration has generated a steric conflict between the ligand and these two proteins, thus impacting the ligand's affinity and selectivity. These ligands have also shown an exceptional selectivity against cathepsin D (>5000-fold) as well as the other aspartyl proteases mentioned. One of the more potent compounds (S)-39 displayed an IC(50) value for BACE1 of 10nM, and exhibited cellular activity with an EC(50) value of 130nM in the ELISA assay. Di-substituted pyridinyl aminohydantoins as potent and highly selective human beta-secretase (BACE1) inhibitors.,Malamas MS, Barnes K, Johnson M, Hui Y, Zhou P, Turner J, Hu Y, Wagner E, Fan K, Chopra R, Olland A, Bard J, Pangalos M, Reinhart P, Robichaud AJ Bioorg Med Chem. 2010 Jan 15;18(2):630-9. Epub 2009 Dec 6. PMID:20045648[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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