A. Anoctamine channels
The recently discovered anoctamines constitute a large family of calcium-activated chloride channels. Although the 10 family members in human are broadly expressed, their specific role in various physiological processes is not well understood. The up-regulation of certain anoctamines in cancers underlines their role as possible pharmacological targets.
We aim at the first detailed structural characterization of this important class of ion channels. Since anoctamine channels are only found in eukaryotic organisms (with few family members in yeast), we need to establish several eukaryotic protein overexpression and purification protocols.
We also plan a functional characterization of anoctamines by different electrophysiological techniques. The ultimate goal will be the determination of the crystal structure of full-length anoctamines followed by structure-based design of channel modulators.
B. Divalent metal ion transporters
Dysfunction of the divalent metal ion transporters DMT1 and NRAMP1 are associated with iron deficiency anemia, iron overload disorders, neurodegenerative diseases (e.g., Parkinson's disease and Alzheimer’s disease), autoimmune and inflammatory diseases (e.g., rheumatoid arthritis).
These pathophysiological implications highlight the need to unravel the structure and mechanistic understanding of iron transporters, and to design novel inhibitors or activators for the treatment of iron-related disorders.
The initial focus will be on the structural biology of DMT transporters using close prokaryotic homologues of the family. In parallel, we will proceed with the compound screening. In a later phase, we will concentrate on the overexpression, purification and crystallization of mammalian DMT transporters.
The X-ray structures of mammalian DMTs will be used for the design and characterization of novel inhibitors and/or allosteric modulators of human DMT1 (see projects 10A and 10D).