PhD in Biosciences (# of pos: 3)

Interdisciplinary PhD positions at the Institute of Biochemistry

The Institute of Biochemistry at the Graz University of Technology is looking for three highly motivated PhD candidates with a genuine interest in understanding molecular mechanisms of biochemical processes.

One PhD position is available as a university assistant position involving teaching and research activities in the group of Peter Macheroux. The research project will have a focus on developing highly specific inhibitors of chorismate synthase, the last enzyme of the common shikimate pathway toward the biosynthesis of aromatic compounds, such as phenylalanine, tyrosine and tryptophan. Toward this goal, we will attempt to determine the structure of the enzyme in complex with lead structures to gain insight into the interaction with amino acid residues in the active site in order to improve the affinity of potential inhibitors. This project will be carried out in collaboration with Andreas Winkler (structural biology) and Rolf Breinbauer at the Institute of Organic Chemistry (organic synthesis of inhibitors). The ultimate aim of the project is the development of therapeutically useful drugs targetting chorismate synthase (1,2).

An FWF-funded PhD positions is available in the research group of Gustav Oberdorfer. The groups primary research interests are designing and engineering of biomolecular structures and their function - a multi-facetted effort that combines computational biology, structural biology, biochemistry and biophysics (3, 4). The PhD project will be part of a small local research consortium combining three different disciplines of modern life sciences. In an effort to integrate protein design with optogenetics (group of Andreas Winkler) and tumor immunology (group of Julia Kargl) the successful candidate will employ light responsive dimerization modules to design, engineer and test modern anti-cancer drugs. More specifically, the goal will be to design light-regulated heterodimerization modules that can be linked to different single chain antibodies that would enable T-cell mediated tumor killing with high temporal and spatial precision.

The third PhD position is available in the research group of Andreas Winkler. Objectives in this group revolve around an integrative structural biology approach addressing mechanisms of signal transduction in natural light-regulated enzymes. Understanding principles of sensor-effector modularity and how nature adapts them for diverse requirements, is key to improve success rates of artificial designs for the generation of novel optogenetic tools. In this project, the focus will be set on combining biochemistry and various tools of structural biology (crystallography and hydrogen-deuterium exchange coupled to mass spectrometry) including local collaborations in NMR (Tobias Madl) and cryo-EM (Tea Pavkov-Keller) to address the functional role of structural asymmetry in bacterial red-light photoreceptors (5, 6). Eventually, appreciation of molecular details of structural asymmetry will be helpful for a more rational approach to the design of artificial light regulated functionalities.

All projects provide in-depth, interdisciplinary training in biomedical and biotechnological research in an international and stimulating environment. The thesis projects follow an integrative approach and combine structural biology, enzymology, computational protein design and biophysics to decipher biosynthetic pathways, molecular mechanisms of catalysis and development of biomedical tools, employing a wide range of cutting-edge techniques.

Applicants must hold (or be close to obtaining) an undergraduate degree equivalent to a Master in any discipline of natural, life sciences or computer sciences. The ability to work in a team, initiative, flexibility as well as good organizational and learning skills are required. The selection procedure, all training activities and communications will be in English. Thus, excellent written and spoken English skills are required. Successful applicants will get employed for up to four years (initial contract for one year with the option of prolongation upon successful performance) with a contract that includes social benefits.

Interested applicants should send a motivation letter, CV, one-page summary of their research experience and contact details of two potential referees until the 9th of December 2019 to office.ibc@tugraz.at . Prospective starting dates throughout 2020 can be discussed upon acceptance.

References:

1 – Rodrigues-Vendramini F A V, Marschalk C, Toplak M, Macheroux P, Bonfim-Mendonca P, Svidzinski T I E, Seixas F A V, Kioshima E S. (2019) Promising new antifungal treatment targeting chorismate synthase from Paracoccidioides brasiliensis. Antimicrobial Agents & Chemotherapy 63:1-14.

2 – Bueno P S A, Rodrigues-Vendramini F A V, Toplak M, Macheroux P, Kioshima E S, Seixas F A V. (2019) New inhibitors of chorismate synthase present antifungal activity against Paracoccidioides brasiliensis. Future Microbiology 14:969-980.

3 - Oberdorfer G, Huang P-S, Xu C, Pei X Y, Nannenga B L, Rogers J M, DiMaio F, Gonen T, Luisi B, Baker D. (2014) High thermodynamic stability of parametrically designed helical bundles. Science 346 (6208): 481-485.

4 - Boyken S E, Chen Z, Groves B, Langan R A, Oberdorfer G, Ford A, Gilmore J M, Xu C, DiMaio F, Pereira J H, Sankaran B, Seelig G, Zwart P H, Baker D. (2016) De novo design of protein homo-oligomers with modular hydrogen-bond network–mediated specificity. Science 352 (6286):  680-687.

5 - Gourinchas G, Etzl S, Göbl C, Vide U, Madl T, Winkler A. (2017) Long-range allosteric signaling in red light–regulated diguanylyl cyclases. Sci Adv 3 (3), e1602498.

6 - Gourinchas G, Heintz U, Winkler A. (2018) Asymmetric activation mechanism of a homodimeric red light regulated photoreceptor. eLife 7, e34815.