Dr. Daniel Nietlispach, Department of Biochemistry, University of Cambridge
Tuesday 25th September, 1.00 p.m., Stacey Lecture Theatre 1
G-protein-coupled receptors (GPCRs) are a large family of membrane embedded proteins that activate a multitude of signalling pathways triggering various cellular responses in health and disease. The last decade resulted in a surge of receptor structures mostly through crystallography, helping to shape a static view of these receptors in mostly inactive but also active states, including in complex with the cytoplasmic binding partners heterotrimeric G-proteins, b-arrestins and their mimetics. Despite this wealth of static information, key questions related to GPCR function and mechanism of action persist due to the intrinsically dynamic nature of these receptors.
We use 1H,13C NMR spectroscopy to investigate ligand based activation and basal activity of the b1 adrenergic receptor (b1AR). In our study we find evidence for the existence of novel active receptor states and a level of receptor plasticity in ternary complexes, which can be related to the pharmacological concept of partial agonism. Our NMR data connects receptor activity to the presence of ms-to-ms timescale dynamics and shows b1AR as a highly adaptable molecular signalling entity. Further investigations related to the influence of the membrane protein environment in receptor activation are presented.