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Crystal structure of the Fucosylgalactoside alpha N-acetylgalactosaminyltransferase (GTA, cisAB mutant L266G, G268A) in complex with a novel UDP-Gal derived inhibitor (2GW)Crystal structure of the Fucosylgalactoside alpha N-acetylgalactosaminyltransferase (GTA, cisAB mutant L266G, G268A) in complex with a novel UDP-Gal derived inhibitor (2GW)
Structural highlights
Publication Abstract from PubMedGlycosyltransferases (GTs) are enzymes that are involved, as Nature's glycosylation reagents, in many fundamental biological processes including cell adhesion and blood group biosynthesis. Although of similar importance as other large enzyme families such as protein kinases and proteases, the undisputed potential of GTs for chemical biology and drug discovery has remained largely unrealized to date. This is due, at least in part, to a relative lack of GT inhibitors and tool compounds for structural, mechanistic and cellular studies. In this study, we have used a novel class of GT donor analogues to obtain new structural and enzymological information for a representative blood group GT. These analogues interfere with the folding of an internal loop and the C-terminus which are essential for catalysis. Our experiments have led to the discovery of an entirely new active site folding mode for this enzyme family, which can be targeted in inhibitor development, similar to the DFG motif in protein kinases. Taken together, our results provide new insights into substrate binding, dynamics and utilization in this important enzyme family, which can very likely be harnessed for the rational development of new GT inhibitors and probes. Base-modified donor analogues reveal novel dynamic features of a glycosyltransferase.,Jorgensen R, Pesnot T, Lee HJ, Palcic MM, Wagner GK J Biol Chem. 2013 Jul 8. PMID:23836908[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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