Ligand-gated ion channel receptors in brain diseases
Studies of molecular function and basis for drug design
The goal is to obtain detailed understanding of ligand-gated ion channel receptor structure and function, which is essential for providing a rational basis for design of therapeutic strategies for treating diseases and disorders within the central nervous system. The focus is both on studies of full-length solubilized ionotropic glutamate receptors and Cys-loop receptors (e.g. acetylcholine receptors) and domains thereof.
Structure of acetylcholine binding protein from Lymnaea stagnalis in complex with the antagonist DHE (Shahsavar et al., 2012; pdb-code 4ALX).
Structure of the ligand-binding domain of GluA2 in complex with glutamate and an the allosteric modulator BPAM97 (Krintel et al. 2012; pdb-code 3TDJ).
Diseases and disorders within the brain represent one of the largest and fastest growing areas of unmet medical need. Neurotransmitters play key roles in the complex mechanisms of the central nervous system and interact with e.g. ligand-gated ion channel receptors. These receptors are critically important for the mechanism of fast synaptic transmission. Consequently, therapeutic intervention in receptor signaling has proven beneficial in neurological and psychiatric disorders. In addition to being targeted by marketed smoking cessation aids, the acetylcholine receptors constitute promising targets for the treatment of neurodegenerative and psychiatric disorders. Likewise, the glutamate receptors are promising targets for such disorders, and since 2002 the drug memantine has been in use for treatment of Alzheimer’s disease. Therefore, much effort has been and needs to be directed toward understanding the structure, function and basis for subtype selective drug targeting of these receptors.
The research group
The research group investigates structure, flexibility, activation mechanisms and binding modes of novel agonists, antagonists and allosteric modulators using various techniques, including protein expression in E. coli and insect cells, X-ray crystallography, isothermal titration calorimetry, circular dichroism and computational chemistry, including computer-aided design and virtual screening.