8XGT

Crystal structure of human secretory glutaminyl cyclase in complex with (Z)-3-((1H-benzo[d]imidazol-5-yl)methylene)-4-hydroxyindolin-2-one

これはPDB形式変換不可エントリーです。

8XGT の概要

• エントリーDOI: 10.2210/pdb8xgt/pdb
• 分子名称: Glutaminyl-peptide cyclotransferase, ZINC ION, (3~{Z})-3-(1~{H}-benzimidazol-5-ylmethylidene)-4-oxidanyl-1~{H}-indol-2-one, ... (4 entities in total)
• 機能のキーワード: inhibitor, complex, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 454801.01

構造登録者

Li, G.-B.,Wang, X.-Y. (登録日: 2023-12-15, 公開日: 2024-06-12, 最終更新日: 2024-06-26)

主引用文献

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

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

実験手法

X-RAY DIFFRACTION (2.813 Å)