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Binding of N-acetylglucosamine (GlcNAc) ?1-6-branched oligosaccharide acceptors to ?4-galactosyltransferase I reveals a new ligand binding mode.

ABSTRACT: N-acetyllactosamine is the most prevalent disaccharide moiety in the glycans on the surface of mammalian cells and often found as repeat units in the linear and branched polylactosamines, known as i- and I-antigen, respectively. The ?1-4-galactosyltransferase-I (?4Gal-T1) enzyme is responsible for the synthesis of the N-acetyllactosamine moiety. To understand its oligosaccharide acceptor specificity, we have previously investigated the binding of tri- and pentasaccharides of N-glycan with a GlcNAc at their nonreducing end and found that the extended sugar moiety in these acceptor substrates binds to the crevice present at the acceptor substrate binding site of the ?4Gal-T1 molecule. Here we report seven crystal structures of ?4Gal-T1 in complex with an oligosaccharide acceptor with a nonreducing end GlcNAc that has a ?1-6-glycosidic link and that are analogous to either N-glycan or i/I-antigen. In the crystal structure of the complex of ?4Gal-T1 with I-antigen analog pentasaccharide, the ?1-6-branched GlcNAc moiety is bound to the sugar acceptor binding site of the ?4Gal-T1 molecule in a way similar to the crystal structures described previously; however, the extended linear tetrasaccharide moiety does not interact with the previously found extended sugar binding site on the ?4Gal-T1 molecule. Instead, it interacts with the different hydrophobic surface of the protein molecule formed by the residues Tyr-276, Trp-310, and Phe-356. Results from the present and previous studies suggest that ?4Gal-T1 molecule has two different oligosaccharide binding regions for the binding of the extended oligosaccharide moiety of the acceptor substrate.

SUBMITTER: Ramakrishnan B

PROVIDER: S-EPMC3436570 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Binding of N-acetylglucosamine (GlcNAc) β1-6-branched oligosaccharide acceptors to β4-galactosyltransferase I reveals a new ligand binding mode.

Ramakrishnan Boopathy B Boeggeman Elizabeth E Qasba Pradman K PK

The Journal of biological chemistry 20120627 34

N-acetyllactosamine is the most prevalent disaccharide moiety in the glycans on the surface of mammalian cells and often found as repeat units in the linear and branched polylactosamines, known as i- and I-antigen, respectively. The β1-4-galactosyltransferase-I (β4Gal-T1) enzyme is responsible for the synthesis of the N-acetyllactosamine moiety. To understand its oligosaccharide acceptor specificity, we have previously investigated the binding of tri- and pentasaccharides of N-glycan with a GlcN ...[more]

PMID: 22740701

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Project description:Protein-ligand docking programs can generate a large number of possible binding orientations for each ligand candidate. The challenge is to identify the orientations closest to the native binding mode using a scoring method. Many different scoring functions have been developed for protein-ligand scoring, but their performance on binding mode prediction is often target-dependent. In this study, a statistical approach was employed to provide a confidence measure of scoring performance in finding close to the correct docked ligand orientations. It exploits the fact that the scores provided by an adequately performing scoring function generally improve as the ligand binding modes get closer to the correct native orientation. For such cases, the correlation coefficient of scores versus distances is expected to be highest when the most native-like orientation is used as a reference. This correlation coefficient, called the correlation-based score (CBScore), was used as an indicator of how far the docked pose was from the native orientation. The correlation between the original scores and CBScores as well as the range of CBScores were found to be good measures of scoring performance. They were combined into a single quantity, called the scoring confidence index. High values of the scoring confidence index were indicative of pronounced and relatively smooth binding energy landscapes with easily discernable global minima, resulting in reliable binding mode predictions. Low values of this index reflected rugged energy landscapes making the prediction of the correct binding mode very difficult and often unreliable. The diagnostic ability of the scoring confidence index was tested on a non-redundant set of 50 protein-ligand complexes scored with three commonly employed scoring functions: AffiScore, DrugScore and X-Score. Binding mode predictions were found to be three times more reliable for complexes with scoring confidence indices in the upper half than for cases with values in the lower half of the resulting range of 0-1.6. This new confidence measure of scoring performance is expected to be a valuable tool for virtual screening applications.

Dataset Information

Binding of N-acetylglucosamine (GlcNAc) ?1-6-branched oligosaccharide acceptors to ?4-galactosyltransferase I reveals a new ligand binding mode.

Publications

Binding of N-acetylglucosamine (GlcNAc) β1-6-branched oligosaccharide acceptors to β4-galactosyltransferase I reveals a new ligand binding mode.

Similar Datasets

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