Vereniging het Nederlands Kanker Instituut

Prof. Dr. Titia Sixma
Plesmanlaan 121
1066CX Amsterdam
The Netherlands

The Netherlands Cancer Institute (NKI) is an integrated cancer center with excellent facilities for advanced cell biology, including state of the art transgenic mouse facility, confocal microscopy, live-cell imaging, DNA microarray technology, immuno-EM, biophysics, high-through-put screening and structural biology. The group of Sixma uses a combination of structural, biochemical and biophysical techniques to study protein function at the molecular level. These data, combining structure with functional insight will improve understanding of fundamental processes and create a basis for structure assisted drug design.

The group has, together with Smit (partner 1), initiated the analysis of Acetylcholine binding protein (AChBP) as a model system for studying ligand binding in cys-loop receptors. The AChBP crystal structure presented the first atomic model of a ligand binding domain of these channels and allowed high resolution analysis ligand binding. Now we want to extend the abilities of using AChBP as a tool for studying cys-loop receptors. We will do by studying ligand binding of AChBP to critical nAChR targets with Ulens (partner 3) and Smit (partner 1), by changing the ligand binding site of AChBPs to resemble other cys-loop receptors with Smit (partner 1) and Lummis (partner 5), including heteropentamers and provide new information on ligand binding in other cys-loop receptors. Upon use of AChBP as screening tool for novel ligands we will analyze the interaction by crystallography (with Smit (partner 1), de Esch (partner 17), and Bertrand (partner 12). Next partner >