8XGY
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
This is a non-PDB format compatible entry.
Summary for 8XGY
| Entry DOI | 10.2210/pdb8xgy/pdb |
| Descriptor | Glutaminyl-peptide cyclotransferase, ZINC ION, (3~{Z})-3-(1~{H}-benzimidazol-5-ylmethylidene)-4-[(3~{R})-1-ethanoylpyrrolidin-3-yl]oxy-1~{H}-indol-2-one, ... (4 entities in total) |
| Functional Keywords | inhibitor, complex, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 12 |
| Total formula weight | 456134.71 |
| Authors | Li, G.-B.,Wang, X.-Y. (deposition date: 2023-12-16, release date: 2024-06-12, Last modification date: 2024-06-26) |
| Primary citation | Mou, J.,Ning, X.L.,Wang, X.Y.,Hou, S.Y.,Meng, F.B.,Zhou, C.,Wu, J.W.,Li, C.,Jia, T.,Wu, X.,Wu, Y.,Chen, Y.,Li, G.B. X-ray Structure-Guided Discovery of a Potent Benzimidazole Glutaminyl Cyclase Inhibitor That Shows Activity in a Parkinson's Disease Mouse Model. J.Med.Chem., 67:8730-8756, 2024 Cited by PubMed Abstract: 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, manifested efficacy in mitigating locomotor deficits through reversing dopaminergic neuronal loss, reducing microglia, and decreasing levels of the sQC/gQC substrates, α-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. PubMed: 38817193DOI: 10.1021/acs.jmedchem.4c00049 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.81 Å) |
Structure validation
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