7coz | pdb_00007coz

Crystal Structure of double mutant Y115E Y117E human Secretory Glutaminyl Cyclase in complex with LSB-41

spinqualitylabelsall models 7coz, resolution 1.85Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7coz is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: EDO, Q39, SO4, ZN Gene: QPCT (HUMAN) Activity: Glutaminyl-peptide cyclotransferase, with EC number 2.3.2.5 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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. Publication Abstract from PubMed Alzheimer's disease (AD), a common chronic neurodegenerative disease, has become a major public health concern. Despite years of research, therapeutics for AD are limited. Overexpression of secretory glutaminyl cyclase (sQC) in AD brain leads to the formation of a highly neurotoxic pyroglutamate variant of amyloid beta, pGlu-Abeta, which acts as a potential seed for the aggregation of full length Abeta. Preventing the formation of pGlu-Abeta through inhibition of sQC has become an attractive disease-modifying therapy in AD. In this current study, through a pharmacophore assisted high throughput virtual screening, we report a novel sQC inhibitor (Cpd-41) with a piperidine-4-carboxamide moiety (IC50 = 34 muM). Systematic molecular docking, MD simulations and X-ray crystallographic analysis provided atomistic details of the binding of Cpd-41 in the active site of sQC. The unique mode of binding and moderate toxicity of Cpd-41 make this molecule an attractive candidate for designing high affinity sQC inhibitors. Piperidine-4-carboxamide as a new scaffold for designing secretory glutaminyl cyclase inhibitors.,Dileep KV, Sakai N, Ihara K, Kato-Murayama M, Nakata A, Ito A, Sivaraman DM, Shin JW, Yoshida M, Shirouzu M, Zhang KYJ Int J Biol Macromol. 2020 Dec 27;170:415-423. doi:, 10.1016/j.ijbiomac.2020.12.118. PMID:33373636 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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