Publication details
The GlcNAc-TV Glycosyltransferase Homology Model Strucutre
| Authors | |
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| Year of publication | 2016 |
| Type | Conference abstract |
| MU Faculty or unit | |
| Citation | |
| Description | Structural diversity of complex-type N-linked oligosaccharides begins with GlcNAc branching of the trimannosyl core by the glycosyltransferase GlcNAc-TV. The enzyme UDP-N-acetylglucosamine: alpha-D-mannoside beta-1-6 N-acetylglucosaminyltransferase V (GnT-V) catalyzes the transfer of GlcNAc from the UDP-GlcNAc donor to the alpha-1-6-linked mannose of the trimannosyl core structure of glycoproteins to produce the beta-1-6-linked branching of N-linked oligosaccharides. The transfer occurs with inversion of the anomeric configuration and is metal-ion-independent. The creation of the beta-1-6- linkage is crucial for further elongation of the carbohydrate chains of N-glycans and biosynthesis of polylactosamine chains terminating with various sequences, including Lewis antigens. beta-1-6-GlcNAc-branched N-glycans are associated with cancer growth and metastasis. Therefore, the inhibition of GnT-V represents a key target for anti-cancer drug development. However, the development of potent and specific inhibitors of GnT-V is hampered by the lack of information on the three-dimensional structure of the enzyme and on the binding characteristics of its substrates. Here we present the 3-D structure of GnT-V as a result of homology modeling. Various alignment methods, docking the donor and acceptor substrates, and molecular dynamics simulation were used to construct seven homology models of GnT-V and characterize the binding of its substrates. The best homology model is consistent with available experimental data. The three-dimensional model, the structure of the enzyme catalytic site and binding information obtained for the donor and acceptor can be useful in studies of the catalytic mechanism and design of inhibitors of GnT-V. |
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