Plenary Lecture
Discovery of Selective Ligands Probing Structural and Functional Properties of GPCRs

Approximately 30 % of the drugs on the market exert their biological activities upon binding to G protein-coupled receptors (GPCRs). The first X-ray crys­tal structures of druggable GPCRs in complex with ligands provide a basis for the investigation of molecular determinants responsible for affinity and selectivity of ligands [1]. Moreover, the structures of different activity states of GPCRs allow us to identify molecular interactions discriminating between inverse agonists, anta­go­nists and agonists. These fundamental results also contribute to the rational discovery of drugs selectively binding to particular conformational states.

We develop highly specific agonists and antagonists for monoaminergic and peptidergic GPCRs and use them as molecular probes for structural and functional investigations and for structure-function relationship studies. As an example, we established a disulfide based tag for the stabilization of a heterocyclic agonist bound low-affinity state of the b₂-adrenoreceptor leading to the X-ray crystal structure of an agonist bound G-protein coupled receptor [2]. Extending this strategy to GPCR-activating neurotransmitters and hormones, covalent catecholamines were constructed leading to the crystal structure of the β₂–adrenergic receptor (β₂AR) in complex with an irreversibly bound derivative of the endogenous ligand norepinephrine [3].

The seminar will show very recent developments in the design, synthesis and biological investigation of molecular probes used to elucidate and control G protein-coupled receptors.

1. Granier, S., Kobilka, B.: Nat Chem Biol. 2012, 8: 670-673
2. 2. Rosenbaum, DM. et al.: Nature 2011, 469: 236-240
3. Weichert, D. et al.: Proc. Natl. Acad. Sci. USA 2014, 111, 10744-10748