Sialyllactose complexation with

The crystal structure of the A-terminal domain of sialoadhesin in complex with sialyllactose as ligand has been solved at 1.85 A resolution [222]. The structure of the immunoglobulin domain contained in this receptor conforms to the V-set immunoglobulin-like fold but contains several distinctive features. The carboxylate of sialic acid forms a salt bridge with a side chain of Arg97 (O Fig. 18). 

The exact sugar conformation in the ES complex of GH 33 enzymes seems to vary from substrate to substrate. Thus, complexes of 4-methylumbelliferyl N-acetyl-a-neuraminide in complex with the (inactive) acid-base mutant of the T. cruzi tf(2 .s-sialidase reveal a conformation, whereas the complex with sialyllactose has a 82 5 ring these are next to each other on the pseudoro-tational itinerary (Figure 2.6b). A possible conformational trajectory for the pyranose ring in these enzymes is 82 5 (ES complex) (probably most stable conformation of the sialosyl cation, with NElAc and OH pseudoequa-torial) Cs (glycosyl-enzyme intermediate). This would result in most of the motion of the substrate relative to enzyme in the course of catalysis being in the carbon which is being substituted, in the normal way. 

Yuan P, Thompson TB, Wurzburg BA, Paterson RG, Lamb RA, Jardetzky TS (2005) Structural studies of the parainfluenza vims 5 hemagglutinin-neuraminidase tetramer in complex with its receptor, sialyllactose. Stmeture 13 803-815... 

Figure 4. Interactions at the 3 sialyUactose binding site. A. Spacefilling models of Sn and MAG showing the regions of the V-set domain of each protein that form the binding site for 3 sia-lyllactose. The model for Sn is based on the crystal structure whereas the model for MAG has been built using the Sn model as a template (A. May, personal communication), followed by changing the conformation of several amino acids to prevent clashes with other amino acid side chains. Shown are amino acids 1-5 (A strand), 40-44 (C/C strands), 97-112 (C-terminal part of F strand and N-terminal part of G strand) of Sn, shaded as indicated, and the bound 3 -sialyllactose (light). The same scheme is used for the MAG model. B. Diagram depicting the interactions between amino acids in the V-set domain of Sn and sialic acid deduced from the crystal structure of the V-set domain complexed with 3 sialyUactose. The sialic acid is shown in thick black lines.

Acknowledgements This work was supported in part by the NCI grant CA-13148. The authors wish to thank Prof. B. Mario Pinto for supplying the originals of some figmes used in this review. The work on sialoadhesin/sialyllactose and UDP-Gal/galctosyltransferase complexes was from a fruitful collaboration with Prof. Thomas Peters at the Medical University of Liibeck. 

Recently, based on inspection of the crystal structure of the complex of TcTS with sialyllactose as substrate, a series of novel C-sialosides were devised as potential inhibitors. Employing ruthenium-catalyzed cross metatheses, a number of derivatives were synthesized and modified [60]. For these novel acceptor mimetics the affinities were studied by surface plasmon resonance (SPR) using immobilized TcTS [61]. Quite interesting values for compounds 103-105 were measured (Fig. 17). Furthermore, using an NMR-based approach [47], considerable reduction of the TcTS reaction rate was observed in the presence of the most active C-sialoside ligand 103 (Fig. 18) [61]. 

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