7CP0
Crystal Structure of double mutant Y115E Y117E human Secretory Glutaminyl Cyclase
Summary for 7CP0
Entry DOI | 10.2210/pdb7cp0/pdb |
Descriptor | Glutaminyl-peptide cyclotransferase, ZINC ION, SULFATE ION, ... (5 entities in total) |
Functional Keywords | glutaminyl-peptide cyclotransferase, sqc, alzheimer's disease, pyroglutamate, transferase |
Biological source | Homo sapiens (Human) |
Total number of polymer chains | 3 |
Total formula weight | 113781.21 |
Authors | Dileep, K.V.,Ihara, K.,Sakai, N.,Shirozu, M.,Zhang, K.Y.J. (deposition date: 2020-08-05, release date: 2021-01-13, Last modification date: 2023-11-29) |
Primary citation | Dileep, K.V.,Sakai, N.,Ihara, K.,Kato-Murayama, M.,Nakata, A.,Ito, A.,Sivaraman, D.M.,Shin, J.W.,Yoshida, M.,Shirouzu, M.,Zhang, K.Y.J. Piperidine-4-carboxamide as a new scaffold for designing secretory glutaminyl cyclase inhibitors. Int.J.Biol.Macromol., 170:415-423, 2020 Cited by PubMed Abstract: 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-Aβ, which acts as a potential seed for the aggregation of full length Aβ. Preventing the formation of pGlu-Aβ 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 (IC = 34 μM). 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. PubMed: 33373636DOI: 10.1016/j.ijbiomac.2020.12.118 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (1.7 Å) |
Structure validation
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