One of the DDC research lines is directed towards the development of compounds towards the pharmaceutically important ligand-gated ion channel family, comprising the nicotinic acetylcholine receptors, the GABAA-, and 5HT3 receptors. In this line of work a structural model of an extracellular ligand-binding domain of the acetylcholine receptor, i.e. the Acetylcholine Binding Protein (AChBP) is used. Recently, the ligand-bound structures, e.g of nicotine-AChBP, have been obtained and have resulted in a detailed characterization of the residues that interact with the ligand.

Both the protein and its 3D structure are excellent starting points for a drug discovery program within the DDC involving computational chemisty, medicinal chemistry, and various types of compound screening technologies.

Selected Publications

Celie, P., van Rossum-Fikkert, S., van Dijk, W.J, Brejc, K., Smit, A.B. and Sixma, T.K. (2003) Nicotine and carbamoylcholine binding to nicotinic acetylcholine receptors as studied by AChBP crystal structures. Neuron 41(6):907-14

Sixma T.K, Smit A.B. (2003) Acetylcholine binding protein (AChBP): a secreted glial protein that provides a high-resolution model for the extracellular domain of pentameric ligand-gated ion channels. Annu. Rev. Biophys. Biomol. Struct. 32:311-34. Review

Smit A.B., Brejc, K., Syed N.I., Sixma T.K. (2003) Structure and function of AChBP, homologue of the ligand-binding domain of the nicotinic acetylcholine receptor. Ann. N Y Acad. Sci. 998:81-92. Review.

Harel, M., Kasher, R., Nicolas, A., Guss, J.M., Balass, M., Fridkin, M., Katchalski-Katzir , E., Smit, A.B., Brejc, K., Sixma, T.K., Sussman, J., and Fuchs, S. The structure of the binding site of the acetylcholine receptor as visualized in the X-ray structure of a complex between bungarotoxin and a high affinity mimotope peptide. Neuron 32, 265-75.

Smit, A.B., Syed, N.I., Schaap, D., Van Minnen, J., Klumperman, J., Kits, K.S., Lodder, H., Van der Schors, R.C., Van Elk, R., Sorgedrager, B., Brejc, K., Sixma, T.K. and Geraerts, W.P.M. (2001) A glia-derived modulator of cholinergic synaptic transmission. Nature 411, 261-268.

Brejc, K., Van Dijk, W.J., Klaassen, R.V., Schuurmans, M., Van der Oost, J., Smit, A.B. & Sixma, T.K. (2001) Crystal structure of AChBP reveals the ligand-binding domain of nicotinic receptors. Nature 411, 269-276.