Raimund Dutzlerís group of structural biologists focuses on Anoctamin channels, divalent metal ion transporters and vesicular neurotransmitter transporters.
The Anoctamins constitute a large family of gated ion channel, which are exclusively found in eukaryotic organisms and whose molecular identity was only revealed five years ago. In human the family contains 10 members including the calcium-activated chloride channel Ano-1, which was recently proposed as target for the treatment of cystic fibrosis. In addition, the up-regulation of certain Anoctamins in cancers underlines their role as possible pharmacological targets.
The group aims at the first detailed structural characterization of this important class of ion channels. Since Anoctamin channels are only found in eukaryotic organisms (with few family members in yeast), several eukaryotic protein overexpression and purification protocols need to be established. The Dutzler group also plans to functionally characterize Anoctamins by different electrophysiological techniques. The ultimate goal will be the determination of the crystal structure of full-length Anoctamins followed by structure-based design of channel modulators for therapeutic purposes.
Divalent metal ion transporters
Divalent metal ion transporters are vital for iron uptake in enterocytes and for transferrin associated endosomal iron transport in many other cell types (Montalbetti and Hediger et al., Mol Aspects Med, 34, 270-287, 2013). Dysfunction of the human DMT1 is associated with anemia, iron overload disorders, neurodegenerative diseases (e.g., Parkinson's disease and Alzheimerís disease), breast and colorectal cancer and autoimmune and inflammatory diseases (e.g., rheumatoid arthritis). The involvement of DMT1 in these disorders makes the pharmacological modulation of this protein a promising therapeutic strategy.
To gain insight into the architecture of divalent metal ion transporters, the Dutzler group focuses on the structure determination of close prokaryotic homologues of the family. In parallel, the group contributes to the identification of activity modulating compounds using a screening assay based on the uptake of divalent metal ions into proteoliposomes containing the reconstituted transporter. In a later phase, the Dutzler group will concentrate on the overexpression, purification and crystallization of mammalian DMT transporters.
Vesicular neurotransmitter transporters
Vesicular glutamate transporters (VGLUTs) take up glutamate in synaptic vesicles in all glutamatergic neurons, some non-glutamatergic ones and in astrocytes. The 3 known VGLUT isoforms are functionally identical but differently distributed. Deletion of VGLUT1 or 2 is lethal whereas VGLUT3 deletion produces functional impairments. High-affinity VGLUT inhibitors exist, but their therapeutic use in pathologies with glutamatergic hyperfunction such as epilepsy is not recommended as it would suppress excitatory transmission ubiquitously. Therefore, some cell-type specific targeting of these transporters may represent a promising therapeutic strategy.
The Dutzler group has the aim to solve the structure of a mammalian VGLUT homologue. This would lay the foundation to the design of highly specific small molecule binders by structure-based drug design for co-crystallization as well as therapeutic purposes. Also, the group contributes to the screening of chemical compounds using proteoliposomes-based approaches.