9KMB
Crystal structure of human glutaminyl cyclase in complex with N-(2-(1H-imidazol-5-yl)ethyl)-4-methoxybenzenesulfonamide
This is a non-PDB format compatible entry.
Summary for 9KMB
| Entry DOI | 10.2210/pdb9kmb/pdb |
| Descriptor | Glutaminyl-peptide cyclotransferase, ZINC ION, ~{N}-[2-(1~{H}-imidazol-5-yl)ethyl]-4-methoxy-benzenesulfonamide, ... (4 entities in total) |
| Functional Keywords | glutaminyl cyclase, sqc, human secretory glutaminyl cyclase, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 3 |
| Total formula weight | 113712.41 |
| Authors | |
| Primary citation | Wu, J.W.,Ning, X.L.,Tang, B.D.,Chen, Y.T.,Yang, Z.B.,Meng, F.B.,Zhou, C.,Yu, J.L.,Li, R.,Li, Z.,Li, G.B. Deciphering Glutaminyl Cyclase Catalytic Pathways Enables Recognition of Anchor Pharmacophores for Inhibitor Discovery. J.Chem.Inf.Model., 65:5006-5018, 2025 Cited by PubMed Abstract: Glutaminyl cyclases are responsible for N-terminal pyroglutamate modifications of various protein/peptide substrates, influencing their metabolic stability or biological functions. However, the precise chemical pathways by which glutaminyl cyclases catalyze the conversion of N-terminal glutamine/glutamate to pyroglutamate are not yet fully understood. We initially identified the catalytically essential components by cross-species structural analysis, followed by ab initio quantum mechanics/molecular mechanics (QM/MM) calculations of human secretory glutaminyl cyclase (sQC) with two tripeptide substrates, and . The results revealed that sQC processes similar reaction pathways for and , but with distinctly different reaction energy barriers. In both reaction pathways, the catalytic triad E201 directly mediates multiple proton transfers, while D248 and D305 primarily maintain the orientation of the triad and stabilize substrate binding. Based on the anchor pharmacophores recognized by the analysis of sQC catalytic intermediates, we successfully identified the imidazole-sulfonamide inhibitors that mimic substrate binding, as validated by cocrystallographic analysis. PubMed: 40368832DOI: 10.1021/acs.jcim.5c00498 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.28 Å) |
Structure validation
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