AbstractsBiology & Animal Science

G protein-coupled receptors (GPCRs) are the key therapeutic targets for thirty to forty percent of all current marketed pharmaceutical drugs developed to cure many acute or chronic diseases. Investigations of naturally occurring in addition to mutations gathered from in vitro mutagenesis studies provide insight into the causes of human genetic diseases and provide novel perspectives for pharmacological strategies targeted at either mutant or wild type GPCRs. A GPCR subfamily, the glycoprotein hormone receptors (GPHRs) and the nucleotide receptor P2Y12 were in the focus of this thesis. Naturally occurring pathogenic mutations in GPHRs have been identified as the cause of several endocrine diseases. One member of this subfamily, the thyrotropin receptor, is a key regulator of thyroid function, and the most prominent disorders related to this receptor are congenital hyper- or hypothyroidism and thyroid cancer. Activation of the P2Y12 triggers platelet aggregation and thus this receptor plays a crucial role upon injury or thrombosis. Defects in the gene encoding for the P2Y12 are often responsible for congenital bleeding disorders. Structural and functional studies of these receptors that elucidate the relevance of particular genetic variants pave the way for deriving more general, overarching mechanisms for other GPCRs. The structural elucidation of GPCRs facilitates the overall understanding of the functional and/or structural importance of certain residues. During recent years, family A GPCRs have been characterized in various studies thus generating a huge amount of data, which will even continue to increase in the future. This particularly concerns: i) the number of available functional data from mutagenesis studies, ii) the deposition and analysis of clinically relevant sequence variants, iii) the availability of complete genomes and thus sequence data of various species in the course of genome projects, and iv) the further structural elucidation of GPCRs by X-ray crystallographic analysis or nuclear magnetic resonance spectroscopy. Tools for the analysis of these comprehensive and non-uniformly stored data are rare, however necessary to analyze the impact of genetic variants on diverse cellular processes. Affected are, for example, ligand binding, receptor expression, G protein coupling, receptor desensitization and receptor recycling. The combination of mutagenesis data with sequence and structural information allows for the identification of receptor modifications altering wild type receptor function. Furthermore, amino acid variations that are tolerated by the biological system, leaving the receptor function unchanged, can be determined. The computational approaches developed in this thesis for linking and unifying these completely different datasets create extremely valuable resources facilitating the visualization, analysis and extraction for expert as well as non-expert users. A mutation database for the GPHRs has been decisively advanced (SSFA-GPHR, available at http://www.ssfa-gphr.de). In addition,…