Sialic acid-binding site

Burmeister, W. P., Guilligay, D., Cusack, S., Wadell, G., and Amberg, N. (2004). Crystal structure of species D adenovirus fiber knobs and their sialic acid binding sites. J. Virol. 78, 7727-7736. 

Tang, S., Shen, Y. J., DeBellard, M. E., Mukhopadhyay, G., Salzer,J. L., Crocker, P. R., and Filbin, M. T. (1997). Myelin-associated glycoprotein interacts vdth neurons via a sialic acid binding site at ARG118 and a distinct neurite inhibition site./ Cell Biol. 138, 1355-1366. 

Fig. (3). Uie HAl subunits of each HA molecule form the head of protein that contains sialic acids binding sites, top left, and antibodies binding sites, top right (reproduced from Nature with the permission of McMillan Publi iers).

It has been proposed that simple non-carbohydrate analogues containing the carboxylate and the acetylamino groups attached to a cyclic backbone spacer would be suflSdent to generate lead compoimds for further elaboration as NA inhibitors. The spacer would need to orient correctly these groups as found in bound DANA. It has been also required thad such compounds adopt a planar structure near the carboxylate to mimic the transition state and be able to present additional side-chain functionality for interaction with other conserved amino acid residues in the sialic acid binding site. 

Given the 3D structure of TcTS, inhibitors may be directed to the sialic acid binding site or to the galactose-acceptor site. 

Varghese JN, Colman PM, van Donkelaar A, Blick TJ, Sahasrabudhe A, McKimm-Breschkin JL. Structural evidence for a second sialic acid binding site in avian influenza virus neuraminidases. Proc Natl Acad Sci USA 1997 94 11808-11812. 

The geometry of the sialic acid binding site is stabilised by a second shell of largely conserved residues which interacts with the above mentioned residues by hydrogen bonds and salt bridges. 

Fig. 1 Sialic acid binding sites of the hemagglutinin (a) and the neuraminidase (b) of influenza A virus and the hemagglutinin-esterase-fusion protein of influenza C virus (c). Molecular surfaces of HA and HEF trimers and the NA tetramer are shown. Receptor-binding sites of HA, HEF and the hemadsorption site of NA are colored ye/tow. The catalytic sites of NA and HEF are colored green. Sialic acid moieties in the binding sites of HA and NA are shown as stick models. The figtffe is based on crystal structures IMQM, 1W20, and IFLC from Protein Data Bank...

Zaitsev V, von Itzstein M, Groves D, Kiefel M, Takimoto T, Portner A, Taylor G (2004) Second sialic acid binding site in Newcastle disease vims hemagglutinin-neuiaminidase implications for fusion. J Virol 78 3733-3741... 

Burmeister WP, Guilligay D, Cusack S, Wadell G, Amberg N (2004) Crystal stracture of species D adenovims fiber knobs and their sialic acid binding sites. J Virol 78 7727-7736... 

Nath D., van der Merwe P. A., Kelm S., Bradfield P. and Crocker P. R. (1995) The amino-terminal immunoglobulin-like domain of sialoadhesin contains the sialic acid binding site. Comparison with CD22, J. Biol. Chem. 270 26184-26191. 

Figure 5. Potential cu-inhibition of siglec binding sites. Diagram illustrating how extension of the sialic acid binding site of siglecs away from the plasma membrane could be important in regulation of cell ll interactions. See text for further discussion.

Jorgensen, E. D., Collins, P. L., and lomedico, P. T., 1987, Cloning and nucleotide sequence of Newcastle disease virus hemagglutinin-neuraminidase mRNA Identification of a putative sialic acid binding site. Virology 156 12-24. 

---