4acu

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<StructureSection load='4acu' size='340' side='right'caption='[[4acu]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
<StructureSection load='4acu' size='340' side='right'caption='[[4acu]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4acu]] 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=4ACU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ACU FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4acu]] 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=4ACU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ACU FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=QN7:(8S)-3,3-DIFLUORO-8-(2-FLUORO-3-METHOXYBIPHENYL-3-YL)-8-PYRIDIN-4-YL-2,3,4,8-TETRAHYDROIMIDAZO[1,5-A]PYRIMIDIN-6-AMINE'>QN7</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.75&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1fkn|1fkn]], [[1m4h|1m4h]], [[1py1|1py1]], [[1sgz|1sgz]], [[1tqf|1tqf]], [[1ujj|1ujj]], [[1ujk|1ujk]], [[1w50|1w50]], [[1w51|1w51]], [[1xn2|1xn2]], [[1xn3|1xn3]], [[1xs7|1xs7]], [[1ym2|1ym2]], [[1ym4|1ym4]], [[2b8l|2b8l]], [[2b8v|2b8v]], [[2fdp|2fdp]], [[2va5|2va5]], [[2va6|2va6]], [[2va7|2va7]], [[2vie|2vie]], [[2vij|2vij]], [[2viy|2viy]], [[2viz|2viz]], [[2vj6|2vj6]], [[2vj7|2vj7]], [[2vj9|2vj9]], [[2vkm|2vkm]], [[2vnm|2vnm]], [[2vnn|2vnn]], [[2wez|2wez]], [[2wf0|2wf0]], [[2wf1|2wf1]], [[2wf2|2wf2]], [[2wf3|2wf3]], [[2wf4|2wf4]], [[2wjo|2wjo]], [[2xfi|2xfi]], [[2xfj|2xfj]], [[2xfk|2xfk]], [[4acx|4acx]]</div></td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=QN7:(8S)-3,3-DIFLUORO-8-(2-FLUORO-3-METHOXYBIPHENYL-3-YL)-8-PYRIDIN-4-YL-2,3,4,8-TETRAHYDROIMIDAZO[1,5-A]PYRIMIDIN-6-AMINE'>QN7</scene></td></tr>
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<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>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4acu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4acu OCA], [https://pdbe.org/4acu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4acu RCSB], [https://www.ebi.ac.uk/pdbsum/4acu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4acu ProSAT]</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=4acu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4acu OCA], [https://pdbe.org/4acu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4acu RCSB], [https://www.ebi.ac.uk/pdbsum/4acu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4acu ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[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>
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[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The evaluation of a series of bicyclic aminoimidazoles as potent BACE-1 inhibitors is described. The crystal structures of compounds 14 and 23 in complex with BACE-1 reveal hydrogen bond interactions with the protein important for achieving potent inhibition. The optimization of permeability and efflux properties of the compounds is discussed as well as the importance of these properties for attaining in vivo brain efficacy. Compound (R)-25 was selected for evaluation in vivo in wild type mice and 1.5h after oral co-administration of 300mumol/kg (R)-25 and efflux inhibitor GF120918 the brain Abeta40 level was reduced by 17% and the plasma Abeta40 level by 76%.
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Aminoimidazoles as BACE-1 inhibitors: The challenge to achieve in vivo brain efficacy.,Swahn BM, Holenz J, Kihlstrom J, Kolmodin K, Lindstrom J, Plobeck N, Rotticci D, Sehgelmeble F, Sundstrom M, Berg S, Falting J, Georgievska B, Gustavsson S, Neelissen J, Ek M, Olsson LL, Berg S Bioorg Med Chem Lett. 2012 Mar 1;22(5):1854-9. Epub 2012 Jan 28. PMID:22325942<ref>PMID:22325942</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4acu" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Memapsin 2]]
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[[Category: Berg S]]
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[[Category: Berg, S]]
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[[Category: Ek M]]
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[[Category: Berg, S von]]
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[[Category: Falting J]]
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[[Category: Ek, M]]
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[[Category: Georgievska B]]
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[[Category: Falting, J]]
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[[Category: Gustavsson S]]
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[[Category: Georgievska, B]]
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[[Category: Holenz J]]
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[[Category: Gustavsson, S]]
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[[Category: Kihlstrom J]]
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[[Category: Holenz, J]]
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[[Category: Kolmodin K]]
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[[Category: Kihlstrom, J]]
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[[Category: Lindstrom J]]
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[[Category: Kolmodin, K]]
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[[Category: Neelissen J]]
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[[Category: Lindstrom, J]]
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[[Category: Olsson LL]]
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[[Category: Neelissen, J]]
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[[Category: Plobeck N]]
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[[Category: Olsson, L L]]
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[[Category: Rotticci D]]
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[[Category: Plobeck, N]]
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[[Category: Sehgelmeble F]]
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[[Category: Rotticci, D]]
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[[Category: Sundstrom M]]
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[[Category: Sehgelmeble, F]]
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[[Category: Swahn B]]
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[[Category: Sundstrom, M]]
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[[Category: Von Berg S]]
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[[Category: Swahn, B]]
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[[Category: Alzheimer's disease]]
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[[Category: Hydrolase]]
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Revision as of 07:14, 1 May 2024

Aminoimidazoles as BACE-1 Inhibitors. X-RAY CRYSTAL STRUCTURE OF BETA SECRETASE COMPLEXED WITH COMPOUND 14

PDB ID 4acu

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