6gbx
From Proteopedia
Crystal structure of human glutaminyl cyclase variant Y115E-Y117E in complex with SEN177
Structural highlights
Function[QPCT_HUMAN] Responsible for the biosynthesis of pyroglutamyl peptides. Has a bias against acidic and tryptophan residues adjacent to the N-terminal glutaminyl residue and a lack of importance of chain length after the second residue. Also catalyzes N-terminal pyroglutamate formation. In vitro, catalyzes pyroglutamate formation of N-terminally truncated form of APP amyloid-beta peptides [Glu-3]-beta-amyloid. May be involved in the N-terminal pyroglutamate formation of several amyloid-related plaque-forming peptides.[1] [2] [3] Publication Abstract from PubMedRecent evidence links the role of human glutaminyl cyclase (hQC) to the amyloidogenic process involved in Alzheimer's disease (AD). hQC is a zinc enzyme present in neuronal tissue and its activity is responsible for the cyclization of N-terminal Gln or Glu beta-amyloid peptides, leading to N-pyroglutamic acid peptides (pE-Abeta) that is probably a crucial event in the initiation and progress of the disease. Indeed, pE-containing peptides exhibit an elevated neurotoxicity and a tendency to aggregate. These observations render hQC inhibition an attractive strategy for developing new molecules active against AD. We present here the crystal structure of hQC in complex with SEN177, a newly designed molecule. The SEN177-binding mode to hQC differs from that of the known hQC inhibitors. SEN177 Ki on hQC is 20 nM, comparable or better than that of the most potent known hQC inhibitors PBD150 and PQ912. In addition, SEN177 already demonstrated relevant pharmacological properties in in vivo models of Huntington's disease. All these properties make SEN177 an important scaffold for developing molecules acting on AD and related diseases. The structure of the human glutaminyl cyclase-SEN177 complex indicates routes for developing new potent inhibitors as possible agents for the treatment of neurological disorders.,Pozzi C, Di Pisa F, Benvenuti M, Mangani S J Biol Inorg Chem. 2018 Aug 21. pii: 10.1007/s00775-018-1605-1. doi:, 10.1007/s00775-018-1605-1. PMID:30132075[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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