G PROTEIN-COUPLED RECEPTORS: STRUCTURE-FUNCTIONAL ANALYSIS OF DISEASE-CAUSING MUTATIONS

The activation of different classes of plasma membrane receptors regulates the activity of practically every cell of the body. The vast majority of these receptors belong to the superfamily of G protein coupled receptors (GPCRs) which, at current estimates, account for about 1% of the genes present in a mammalian genome. Dysregulation of GPCR function is associated with a growing number of human diseases. The investigation is centered on three GPCR subfamilies: a) the adrenergic receptors (ARs), b) the gonadotropin receptors (LHR and FSHR), and c) the V2 vasopressin receptor (V2R). An approach that integrates advanced computational biology and bioinformatics with mutational, biophysical and biochemical experiments will be used. The main objectives are: a) to obtain enough molecular information to open new therapeutic perspectives, from rational design of new drugs to the engineering of molecules with curative potential in gene therapy experiments, and b) to elaborate molecular models able to predict the functional effect of receptor mutations and their propensity to induce defective behaviour with pathological implications. The simultaneous investigation of diverse members of the same family of molecules will add to the study the power of comparative analysis, and will help to focus on the general features that underly defective behaviour. The three branches of this project are expected to converge into conclusions that have wider relevance and likely to be applicable to the whole family of GPCR. The theoretical models and the inherent computer simulation protocols will be made available to the scientific community.