X-ray Structure-Guided Discovery of a Potent Benzimidazole Glutaminyl Cyclase Inhibitor That Shows Activity in a Parkinson’s Disease Mouse Model
Jun Mou,
Xiang-Li Ning,
Xin-Yue Wang
et al.
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… Show more
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