Estudio de los micro-dominios funcionales e interacción con ligandos en Receptores Acoplados a Proteínas G (gpcrs) mediante herramientas bioinformáticas

Abstract

The G protein-coupled receptors (GPCRs) are one of the largest families of integral membrane proteins in mammals. These receptors are involved in the translation of numerous endogenous and exogenous signals into cellular responses as part of a complex signaling system that involves a great diversity of ligands and other cellular proteins. Despite the low sequence identity between members of the GPCRs family, there is a high structural similarity, characterized by a conserved molecular architecture of seven transmembrane helices (7 TM). In the present work we investigate the dynamics, modes of interaction with ligands and structural sensitivity to mutations of the 7 TM molecular architecture in GPCRs. To achieve this goal, a set of computational biology tools has been employed and the theoretical results have been verified with experimental data from literature and from collaborations with other research groups. As a result of our work, the functional micro-domains and ligand interacting modes in the human cannabinoid receptor type 1 (CBI R) have been characterized. In adittion, a comprehensive study of the molecular basis of ligands dissociation and potential allosteric sites in human beta-adrenergic receptors was acomplished. On the other hand, the study of the solvation properties of chemical compounds has been exploited in the design of synthetic ligands with increasing affinity for the human serotonin receptor type 4 (5HT4R). Finally, we have identified and characterized a new mutation in the human melanocortin receptor type 2 (MC2R) associated to a familial glucocorticoid deficiency disorder. Most of our theoretical results reveal important attributes of the 7 TM architecture that are crucial in the GPCRs activation and ligand interaction mechanisms, and highlight the importance of computational biology methods in the study of this family of receptors

Date of Award	17 Oct 2012
Original language	Spanish
Awarding Institution	Universitat Autònoma de Barcelona (UAB) Universidad Nacional Andrés Bello
Supervisor	Tomas Perez-Acle (Director) & Xavier Deupi Corral (Director)