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8XGB

Crystal structure of human secretory glutaminyl cyclase in complex with (S)-1-(1H-benzo[d]imidazol-5-yl)-5-(4-propoxyphenyl)imidazolidin-2-one

This is a non-PDB format compatible entry.
Summary for 8XGB
Entry DOI10.2210/pdb8xgb/pdb
DescriptorGlutaminyl-peptide cyclotransferase, ZINC ION, (5~{S})-1-(3~{H}-benzimidazol-5-yl)-5-(4-propoxyphenyl)imidazolidin-2-one, ... (4 entities in total)
Functional Keywordsinhibitor, complex, transferase
Biological sourceHomo sapiens (human)
Total number of polymer chains1
Total formula weight38117.35
Authors
Li, G.-B.,Wang, X.-Y. (deposition date: 2023-12-15, release date: 2024-06-12, Last modification date: 2024-06-26)
Primary citationMou, 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: 38817193
DOI: 10.1021/acs.jmedchem.4c00049
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (3.24 Å)
Structure validation

231029

건을2025-02-05부터공개중

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