G-protein coupled receptors (GPCRs) are important drug targets as they are involved in almost every physiological process. When a drug binds to a GPCR, it stabilizes conformational states which are characterized by the engagement of distinct allosteric networks. Specific receptor states allow the GPCR to interact with intracellular transducers which trigger selected signalling cascades in the cell. Typically, a GPCR regulates more than one transduction pathway. Whereas the modulation of some pathways may lead to beneficial effects in a disease condition, others may cause undesired effects. Current research focuses on obtaining molecules that act only on disease-related pathways while preserving other pathways at their physiological level (so-called biased ligands) . Such ligands are considered to be promising candidates for more efficient and safer treatments. However, the molecular mechanism of how signalling bias is communicated through an allosteric network upon ligand binding remains elusive. For this purpose, we perform a network analysis of residue-residue communication within the receptor using mutual information under different signalling conditions. First data suggest that the capacity of GPCRs to initiate G-protein dependent pathways is encoded in the mutual information between β1 dihedrals of specific residues. All in all, a more detailed understanding of the relationship between network communication and signalling bias can help accelerate the rational design of new generation drugs. S. Isogai, X. Deupi, C. Opitz, F. M. Heydenreich, C.-J. Tsai, F. Brueckner, G. F. X. Schertler, D. B. Veprintsev, and S. Grzesiek, “Backbone NMR reveals allosteric signal transduction networks in the β1-adrenergic receptor,” Nature, vol. 530, pp. 237–241, feb 2016.  T. H. Kim, K. Y. Chung, A. Manglik, A. L. Hansen, R. O. Dror, T. J. Mildorf, D. E. Shaw, B. K. Kobilka, and R. S. Prosser, “The Role of Ligands on the Equilibria Between Functional States of a G Protein-Coupled Receptor,” Journal of the American Chemical Society, vol. 135, pp. 9465–9474, jun 2013.
Adrian Morales-Pastor1, Tomasz Stępniewski1, Tamara Miljuš2, Dmitry B. Veprintsev2, Jana Selent1
1 Research Programme on Biomedical Informatics (GRIB), Universitat Pompeu Fabra (UPF) – Hospital del Mar Medical Research Institute (IMIM), Parc de Recerca Biomèdica de Barcelona (PRBB), Dr. Aiguader, 88, 08003 Barcelona, Spain
2 Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands, UK