biased signaling; GPCRs; beta adrenergic receptors; molecular dynamics simulations; angiotensin receptors
Isogai Shin, Deupi Xavier, Opitz Christian, Heydenreich Franziska M, Tsai Ching-Ju, Brueckner Florian, Schertler Gebhard F X, Veprintsev Dmitry B, Grzesiek Stephan (2016), Backbone NMR reveals allosteric signal transduction networks in the β1-adrenergic receptor., in Nature
, 530(7589), 237-241.
Venkatakrishnan A J, Deupi Xavier, Lebon Guillaume, Heydenreich Franziska M, Flock Tilman, Miljus Tamara, Balaji Santhanam, Bouvier Michel, Veprintsev Dmitry B, Tate Christopher, Schertler Gebhard F X, Babu M Madan (2016), Diverse activation pathways in class A GPCRs converge near the G-protein-coupling region., in Nature
, 536(7617), 484-487.
Malmerberg Erik, M Bovee-Geurts Petra H, Katona Gergely, Deupi Xavier, Arnlund David, Wickstrand Cecilia, Johansson Linda C, Westenhoff Sebastian, Nazarenko Elena, Schertler Gebhard F X, Menzel Andreas, de Grip Willem J, Neutze Richard (2015), Conformational activation of visual rhodopsin in native disc membranes., in Science Signaling
, 8(367), ra26.
Sun Dawei, Flock Tilman, Deupi Xavier, Maeda Shoji, Matkovic Milos, Mendieta Sandro, Mayer Daniel, Dawson Roger J P, Schertler Gebhard F X, Babu M Madan, Veprintsev Dmitry B (2015), Probing Gαi1 protein activation at single-amino acid resolution., in Nature Structural & Molecular Biology
, 22(9), 686-694.
Ostermaier Martin K, Peterhans Christian, Jaussi Rolf, Deupi Xavier, Standfuss Jörg (2014), Functional map of arrestin-1 at single amino acid resolution., in PNAS
, 111(5), 1825-1830.
Manni Sandro, Mineev Konstantin S, Usmanova Dinara, Lyukmanova Ekaterina N, Shulepko Mikhail A, Kirpichnikov Mikhail P, Winter Jonas, Matkovic Milos, Deupi Xavier, Arseniev Alexander S, Ballmer-Hofer K (2014), Structural and functional characterization of alternative transmembrane domain conformations in VEGF receptor 2 activation., in Structure/Folding and Design
, 22(8), 1077-1089.
G protein-coupled receptors (GPCRs) are a large family of membrane proteins that transmit the information carried by extracellular signals (like natural ligands or therapeutic drugs) into the cell by activating G protein- or arrestin-mediated intracellular signaling pathways. GPCRs are key in cell physiology and constitute one of the most important pharmaceutical targets. Despite their significance, we are just starting to understand the molecular mechanisms by which ligands modulate GPCR activity. For instance, in recent years many researchers have shown that G protein- and arrestin-mediated signaling pathways can be modulated with “biased ligands”. The concept of “biased agonism” has become an important concept of clinical relevance in modern pharmacology, as ligands with biased properties hold promise to become better drugs, with fewer side effects caused by promiscuous activation of cellular signaling pathways. However, design of such biased agonists requires a better understanding at a molecular level on how ligands activate GPCRs. There is ample evidence that GPCRs adopt multiple conformations along their activation pathway. Biased ligands would preferentially stabilize some of these conformations, which would result in a better interaction with a specific intracellular partner, resulting in the preferred activation of a particular signaling pathway.This project aims to gain a better understanding of how biased ligands activate GPCRs. We will focus on the beta adrenergic and angiotensin receptors, where biased signaling is best described. We will combine experimental data from X-ray crystallography and biophysical studies (phi-value analysis and fluorescence spectroscopy) with state-of-the-art (adiabatic biased and well-tempered metadynamics) molecular dynamics simulations to obtain structural information of intermediate active states and to calculate the energy landscapes associated to receptor activation by biased ligands.Our results will allow a more detailed understanding of how biased ligands stabilize specific GPCR active conformations. We expect that this knowledge will facilitate the development of improved therapeutic agents that target GPCRs with improved efficacy and fewer side effects.