Photoswitches and Photoresponsive Ribozymes

The group of Andres Jäschke at IPMB, Heidelberg University, has a long lasting interest in catalysis and regulation by DNA and RNA. We first discovered ribozymes that catalyze as true enzymes the formation of C-C bonds by Diels-Alder reaction (1,2) and used a variety of chemical, biochemical and physical techniques to elucidate their structures and mechanisms (3). We developed combinatorial and rational approaches to modulate the catalytic activity of such RNA enzymes by allosteric principles, and obtained molecular switches that are 50 – 2000-fold activated by the addition of effector molecules (4-6). Recently, we have developed new RNA building blocks that undergo reversible photoisomerization reactions (7). Furthermore, we use photolabile protecting groups to induce (irreversible) switching (8).

The focus of the project is now to develop – by rational design and/or combinatorial selection – Diels-Alderase ribozymes that can be reversibly activated and inactivated by light of different wavelengths. Furthermore, reporter systems will be developed that combine reversible switching of structure formation with a convenient output. A broad spectrum of methods, from multistep organic synthesis, molecular biology techniques to various spectroscopic methods both at the ensemble and at the single-molecule level will be applied, in part in collaboration with leading external researchers.

The successful candidate will be a member of an international, highly motivated team of chemists, biologists, biotechnologists and pharmacists that work at the forefront of RNA chemical biology.

References:

1. Seelig & Jäschke, Chem. Biol. 1999 (6) 167.
2. Seelig et al. Angew. Chem. Int. Ed. 2000 (39) 4576.
3. Serganov et al., Nature Struct. Mol. Biol. 2005 (12) 218.
4. Helm et al. J. Am. Chem. Soc. 2005 (127) 10492.
5. Amontov & Jäschke, Nucleic Acids Res. 2006 (34) 5032.
6. Petermeier & Jäschke, Org. Biomol. Chem. 2009 (7) 288.
7. Singer & Jäschke, J. Am. Chem. Soc. 2010 (132) 8372.
8. Nierth et al., Chem. Commun. 2010 (46) 7975.