About the Research Unit

Heterotrimeric αβγ G proteins, localized at the inner leaflet of the plasma membrane, play a pivotal role for communication of each single cell with its environment. The discovery of G proteins was awarded with the Nobel Prize for Medicine in 1994. G proteins receive input from G protein-coupled receptors (GPCRs) which are embedded in the plasma membrane. GPCRs serve to sense a fascinating variety of extracellular inputs and to translate these into a conformational rearrangement of the receptor’s intracellular face. Here, G proteins “decode” the message and pass it on into the cell interior. In this manner, GPCRs and their cognate G proteins contribute to a multitude of physiological events such as regulation of blood pressure and resistance of the respiratory tract as well as cell motility, metabolism, and proliferation. The high physiological relevance of the GPCR-G protein signaling axis is reflected by the fact that about one third of prescription medicines act via modulation of GPCR function. The Nobel Prize in Chemistry awarded in 2012 for groundbreaking insight into structure and function of GPCRs to Brian Kobilka and Robert Lefkowitz further highlights their therapeutic potential. Stimulated by the enormous progress currently made in the molecular-mechanistic understanding of GPCR function, our consortium endeavors to do the next step, that is shift focus on G proteins as mediators of GPCR-triggered cell responses.

Consequently, we will focus on two main lines of research:

(i)   better understand the role of G proteins under physiological conditions

(ii)  exploit G proteins rather than their linked receptors as novel targets for therapeutic interventions.

Within our multi-disciplinary consortium we therefore aim at the rational design and the generation of novel, cell-permeable signaling inhibitors with selectivity for G protein families. We will generate new inhibitors by combining complementary chemical and biological approaches such as chemical synthesis, as well as combinatorial peptide-, bio- and mutasynthesis. Molecular-mechanistic analyses, elucidation of the mode of action, and target structure-based rational optimization will be employed to identify those inhibitors that can be applied in cellular in vitro and ex vivo/in vivo models. We expect this strategy to provide us with insight into the relevance of individual signaling cascades within complex signaling networks and (patho-)physiological events.