G protein-coupled receptors (GPCRs) are membrane proteins that activate cellular responses by binding to intracellular binding partners. Extracellular binding of ligands control this process by transducing signals across the cell membrane via the receptors. GPCRs are vital in many physiological processes and constitute the most common class of drug targets.
We used the string method with swarms of trajectories to derive the activation pathway and free energy of the β2 adrenergic receptor bound to ligands with different pharmacological properties. Other work includes studies of shared features of activation across class A GPCRs and the effect of sodium modulation on the β2 adrenergic receptor.
We are part of the KAW-funded project “Molecular evolution and design of G protein-coupled receptors with tailored ligand specificity”. The project is a collaboration between four cross-functional groups of researchers, led by Dr Jens Carlsson at Uppsala University. Our group uses MD simulations and data-driven methods to characterize the effect of ligand binding on dopamine receptors activation.
Energy Landscapes Reveal Agonist Control of G Protein-Coupled Receptor Activation via Microswitches. Fleetwood, O., Matricon, P., Carlsson, J. and Delemotte, L. Biochemistry 59(7), 880–891.
Identification of ligand-specific G protein-coupled receptor states and prediction of downstream efficacy via data-driven modeling. Fleetwood, O., Carlsson, J. and Delemotte, L. eLife 2021. 10: e60715.
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