View source for 8xfv


==Crystal structure of human Golgi resident glutaminyl cyclase in complex with (Z)-3-((1H-benzo[d]imidazol-5-yl)methylene)-4-(piperidin-4-yloxy)indolin-2-one==
<StructureSection load='8xfv' size='340' side='right'caption='[[8xfv]], [[Resolution|resolution]] 3.13&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8xfv]] is a 11 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=8XFV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8XFV 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]] 3.13&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1D46:3-(1~{H}-benzimidazol-5-ylmethylidene)-4-piperidin-4-yloxy-1~{H}-indol-2-one'>A1D46</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=8xfv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8xfv OCA], [https://pdbe.org/8xfv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8xfv RCSB], [https://www.ebi.ac.uk/pdbsum/8xfv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8xfv 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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8xfv" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Li G-B]]
[[Category: Wang X-Y]]