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ST3GalI Sialyltransferase Crystal Structure amp MD Simulation Insights
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In this video, we explore the structure and function of ST3Gal-I, a mammalian sialyltransferase enzyme, through a high-quality molecular dynamics (MD) simulation. ST3Gal-I (PDB ID: 2WNB) is shown bound to a disaccharide substrate and CMP (cytidine monophosphate), effectively capturing the enzyme in the act of transferring a sialic acid sugar. We explain the role of ST3Gal-I in glycosylation, detail how sialyltransferases work, and highlight what the MD simulation reveals about the enzyme’s dynamic behavior. • • ST3Gal-I in Glycosylation • Glycans ending in sialic acid decorate many mammalian cell-surface proteins and lipids, influencing processes like cell recognition, adhesion, and immune response. Sialyltransferase enzymes (STs) catalyze the addition of sialic acids to glycans. ST3Gal-I is a β-galactoside α2,3-sialyltransferase that specifically adds sialic acid to the galactose of a core 1 O-glycan (Galβ1-3GalNAc) on glycoproteins. By capping glycans with sialic acid, ST3Gal-I helps terminate glycan chains and modulate biological signaling. Notably, changes in ST3Gal-I activity can alter cell-surface glycosylation; for instance, ST3Gal-I is overexpressed in some cancers, leading to aberrant sialylation of tumor cells. • • Crystal Structure (PDB 2WNB) • The high-resolution crystal structure of porcine ST3Gal-I (PDB 2WNB) reveals how the enzyme binds its substrates. In this structure – the first mammalian sialyltransferase structure solved – ST3Gal-I is co-crystallized with a disaccharide acceptor analog and CMP (the nucleotide leaving group from the donor). The active site shows the disaccharide nestled in a pocket, positioned for sialic acid transfer, while CMP sits in the donor binding site. Conserved sequence motifs (called sialylmotifs) in the enzyme grip the sugar and nucleotide, ensuring proper alignment for catalysis. This structural snapshot provides a foundation for understanding the enzyme’s specificity and mechanism, and even guides the design of selective sialyltransferase inhibitors. • • Catalytic Mechanism • ST3Gal-I operates via an S_N2-like mechanism common to sialyltransferases. It is an inverting glycosyltransferase, meaning the orientation of the sugar linkage flips during the reaction. In the catalytic cycle, the acceptor’s hydroxyl group attacks the anomeric carbon of the donor sialic acid. A catalytic base (a histidine in ST3Gal-I’s active site) simultaneously deprotonates the acceptor’s OH, facilitating the reaction. This one-step nucleophilic attack causes the leaving group (CMP) to depart from the opposite face, producing an α2,3 linkage of sialic acid on the acceptor. Unlike many glycosyltransferases, sialyltransferases do not require a metal ion cofactor for activity. The 2WNB structure captures the enzyme with both product (CMP) and acceptor bound, essentially frozen at the end of the reaction and confirming key aspects of this SN2 mechanism. • • Molecular Dynamics Simulation • A major highlight of this video is the MD simulation that animates ST3Gal-I’s function. By simulating the enzyme in a solvated environment, we can observe its natural motions and how it accommodates the bound ligands in real time. Notably, the simulation shows that active-site loops open to allow substrate binding, then close around the disaccharide and CMP during catalysis. Despite this flexibility, key contacts between the enzyme and the sugar remain intact, maintaining the precise alignment needed for the reaction. We also observe the catalytic histidine shifting position toward the substrate, reinforcing its role in proton transfer. These dynamic insights complement the static crystal structure, yielding a more complete picture of ST3Gal-I’s mechanism. • • Significance • By integrating structural data and MD simulation, this video underscores how combining methods enhances our understanding of biomolecular function. Visualizing ST3Gal-I in motion helps scientists and students alike appreciate the enzyme’s mechanism beyond a static snapshot. Such knowledge is not only academically interesting but also has practical implications. For example, knowing how ST3Gal-I binds and flexes can aid in drug discovery efforts aimed at modulating sialylation – potentially relevant in cancer therapy or anti-inflammatory design. Overall, the detailed view of ST3Gal-I’s structure and dynamics enriches our understanding of glycosylation and the sophisticated molecular machinery of life. • • #glycobiology #moleculardynamics #structuralbiology • References • https://doi.org/10.1074/jbc.M311764200 • https://doi.org/10.1016/s0300-9084(01... • https://doi.org/10.1016/s1074-7613(00... • https://doi.org/10.2147/OTT.S96510 • • https://ortaakarsu.net/ • https://pharmscipulse.com/ • / ortaab • https://scholar.google.com/citations?...
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