7cm0: Difference between revisions
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==Crystal structure of a glutaminyl cyclase in complex with NHV-1009== | ==Crystal structure of a glutaminyl cyclase in complex with NHV-1009== | ||
<StructureSection load='7cm0' size='340' side='right'caption='[[7cm0]]' scene=''> | <StructureSection load='7cm0' size='340' side='right'caption='[[7cm0]], [[Resolution|resolution]] 2.20Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7CM0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7CM0 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7cm0]] is a 4 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=7CM0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7CM0 FirstGlance]. <br> | ||
</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=7cm0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7cm0 OCA], [https://pdbe.org/7cm0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7cm0 RCSB], [https://www.ebi.ac.uk/pdbsum/7cm0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7cm0 ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=G5R:1-(cyclopentylmethyl)-1-[3-methoxy-4-(2-morpholin-4-ylethoxy)phenyl]-3-[3-(5-methylimidazol-1-yl)propyl]urea'>G5R</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=7cm0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7cm0 OCA], [https://pdbe.org/7cm0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7cm0 RCSB], [https://www.ebi.ac.uk/pdbsum/7cm0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7cm0 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/QPCT_HUMAN QPCT_HUMAN] Responsible for the biosynthesis of pyroglutamyl peptides. Has a bias against acidic and tryptophan residues adjacent to the N-terminal glutaminyl residue and a lack of importance of chain length after the second residue. Also catalyzes N-terminal pyroglutamate formation. In vitro, catalyzes pyroglutamate formation of N-terminally truncated form of APP amyloid-beta peptides [Glu-3]-beta-amyloid. May be involved in the N-terminal pyroglutamate formation of several amyloid-related plaque-forming peptides.<ref>PMID:15063747</ref> <ref>PMID:18486145</ref> <ref>PMID:21288892</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The inhibition of glutaminyl cyclase (QC) may provide a promising strategy for the treatment of early Alzheimer's disease (AD) by reducing the amount of the toxic pyroform of beta-amyloid (AbetaNu3pE) in the brains of AD patients. In this work, we identified potent QC inhibitors with subnanomolar IC50 values that were up to 290-fold higher than that of PQ912, which is currently being tested in Phase II clinical trials. Among the tested compounds, the cyclopentylmethyl derivative (214) exhibited the most potent in vitro activity (IC50 = 0.1 nM), while benzimidazole (227) showed the most promising in vivo efficacy, selectivity and druggable profile. 227 significantly reduced the concentration of pyroform Abeta and total Abeta in the brain of an AD animal model and improved the alternation behavior of mice during Y-maze tests. The crystal structure of human QC (hQC) in complex with 214 indicated tight binding at the active site, supporting that the specific inhibition of QC results in potent in vitro and in vivo activity. Considering the recent clinical success of donanemab, which targets AbetaNu3pE, small molecule-based QC inhibitors may also provide potential therapeutic options for early-stage AD treatment. | |||
Discovery of highly potent human glutaminyl cyclase (QC) inhibitors as anti-Alzheimer's agents by the combination of pharmacophore-based and structure-based design.,Van Manh N, Hoang VH, Ngo VTH, Ann J, Jang TH, Ha JH, Song JY, Ha HJ, Kim H, Kim YH, Lee J, Lee J Eur J Med Chem. 2021 Dec 15;226:113819. doi: 10.1016/j.ejmech.2021.113819. Epub, 2021 Sep 8. PMID:34536669<ref>PMID:34536669</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7cm0" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Glutaminyl cyclase|Glutaminyl cyclase]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Ha JH]] | [[Category: Ha JH]] | ||
Revision as of 19:10, 29 November 2023
Crystal structure of a glutaminyl cyclase in complex with NHV-1009Crystal structure of a glutaminyl cyclase in complex with NHV-1009
Structural highlights
FunctionQPCT_HUMAN Responsible for the biosynthesis of pyroglutamyl peptides. Has a bias against acidic and tryptophan residues adjacent to the N-terminal glutaminyl residue and a lack of importance of chain length after the second residue. Also catalyzes N-terminal pyroglutamate formation. In vitro, catalyzes pyroglutamate formation of N-terminally truncated form of APP amyloid-beta peptides [Glu-3]-beta-amyloid. May be involved in the N-terminal pyroglutamate formation of several amyloid-related plaque-forming peptides.[1] [2] [3] Publication Abstract from PubMedThe inhibition of glutaminyl cyclase (QC) may provide a promising strategy for the treatment of early Alzheimer's disease (AD) by reducing the amount of the toxic pyroform of beta-amyloid (AbetaNu3pE) in the brains of AD patients. In this work, we identified potent QC inhibitors with subnanomolar IC50 values that were up to 290-fold higher than that of PQ912, which is currently being tested in Phase II clinical trials. Among the tested compounds, the cyclopentylmethyl derivative (214) exhibited the most potent in vitro activity (IC50 = 0.1 nM), while benzimidazole (227) showed the most promising in vivo efficacy, selectivity and druggable profile. 227 significantly reduced the concentration of pyroform Abeta and total Abeta in the brain of an AD animal model and improved the alternation behavior of mice during Y-maze tests. The crystal structure of human QC (hQC) in complex with 214 indicated tight binding at the active site, supporting that the specific inhibition of QC results in potent in vitro and in vivo activity. Considering the recent clinical success of donanemab, which targets AbetaNu3pE, small molecule-based QC inhibitors may also provide potential therapeutic options for early-stage AD treatment. Discovery of highly potent human glutaminyl cyclase (QC) inhibitors as anti-Alzheimer's agents by the combination of pharmacophore-based and structure-based design.,Van Manh N, Hoang VH, Ngo VTH, Ann J, Jang TH, Ha JH, Song JY, Ha HJ, Kim H, Kim YH, Lee J, Lee J Eur J Med Chem. 2021 Dec 15;226:113819. doi: 10.1016/j.ejmech.2021.113819. Epub, 2021 Sep 8. PMID:34536669[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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