8xgy
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of human Golgi resident glutaminyl cyclase in complex with (R,Z)-3-((1H-benzo[d]imidazol-5-yl)methylene)-4-((1-acetylpyrrolidin-3-yl)oxy)indolin-2-one== | |
| + | <StructureSection load='8xgy' size='340' side='right'caption='[[8xgy]], [[Resolution|resolution]] 2.81Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8xgy]] is a 12 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=8XGY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8XGY FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.81Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1D5C:(3~{Z})-3-(1~{H}-benzimidazol-5-ylmethylidene)-4-[(3~{R})-1-ethanoylpyrrolidin-3-yl]oxy-1~{H}-indol-2-one'>A1D5C</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=8xgy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8xgy OCA], [https://pdbe.org/8xgy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8xgy RCSB], [https://www.ebi.ac.uk/pdbsum/8xgy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8xgy ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The secretory glutaminyl cyclase (sQC) and Golgi-resident glutaminyl cyclase (gQC) are responsible for N-terminal protein pyroglutamation and associated with various human diseases. Although several sQC/gQC inhibitors have been reported, only one inhibitor, PQ912, is currently undergoing clinic trials for the treatment of Alzheimer's disease. We report an X-ray crystal structure of sQC complexed with PQ912, revealing that the benzimidazole makes "anchor" interactions with the active site zinc ion and catalytic triad. Structure-guided design and optimization led to a series of new benzimidazole derivatives exhibiting nanomolar inhibition for both sQC and gQC. In a MPTP-induced Parkinson's disease (PD) mouse model, BI-43 manifested efficacy in mitigating locomotor deficits through reversing dopaminergic neuronal loss, reducing microglia, and decreasing levels of the sQC/gQC substrates, alpha-synuclein, and CCL2. This study not only offers structural basis and new leads for drug discovery targeting sQC/gQC but also provides evidence supporting sQC/gQC as potential targets for PD treatment. | ||
| - | + | X-ray Structure-Guided Discovery of a Potent Benzimidazole Glutaminyl Cyclase Inhibitor That Shows Activity in a Parkinson's Disease Mouse Model.,Mou J, Ning XL, Wang XY, Hou SY, Meng FB, Zhou C, Wu JW, Li C, Jia T, Wu X, Wu Y, Chen Y, Li GB J Med Chem. 2024 May 31. doi: 10.1021/acs.jmedchem.4c00049. PMID:38817193<ref>PMID:38817193</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 8xgy" style="background-color:#fffaf0;"></div> |
| - | [[Category: | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Li G-B]] | ||
| + | [[Category: Wang X-Y]] | ||
Current revision
Crystal structure of human Golgi resident glutaminyl cyclase in complex with (R,Z)-3-((1H-benzo[d]imidazol-5-yl)methylene)-4-((1-acetylpyrrolidin-3-yl)oxy)indolin-2-one
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