Prof. Titia Sixma
Prof. Titia Sixma is Head, Division of Biochemistry Netherlands Cancer Institute. She will be delivering a lecture in the EMBO Global Exchange Lecture Series 2013

Prof. Sixma’s research is aimed at understanding the structural aspects of errors in cell biology that lead to the development of disease. She studies the structure and function of proteins such as acetylcholine binding proteins and complexes in ubiquitin conjugation, DNA mismatch repair and chromatin remodeling, using protein crystallography with complementary biophysical and biochemical techniques.

Abstract: The acetylcholine binding protein (AChBP) is a homolog of the extracellular domain of the nicotinic acetylcholine receptor, and a representative of the cys-loop receptor family, that includes the 5HT3 serotonin receptor and the GABAA receptor. The crystal structure of AChBP was the first crystal structure for any member of this family and today remains the best model for studying high resolution structures of ligand binding to this pharmaceutically important family of ion channels.

Analyzing the binding modes of a number of ligands from nicotine to conotoxins has given us good understanding how this remarkably plastic binding site is used to generate a response to a variety of signals and how receptor subtypes modulate this. More recently we have started to use this model protein for identifying novel ligands, both in vitro and in silico. We have used AChBPs as a scaffold fro fragment growing studies and could show the value of thermodynamic analysis in distinguishing different variants. Finally we identified an aromatic conjugated small molecule that binds AChBP in an ordered π-π stack of 3 identical molecules per binding site, two parallel, and one antiparallel. In this arrangement AChBP stabilizes the assembly of the stack by aromatic contacts with the C-loop and residues in the complementary binding site. This type of supramolecular binding provides a novel paradigm in drug design.