Biochim Biophys Acta Proteins Proteom
April 2021
The β-adrenergic receptor (βAR) is a member of the G protein-coupled receptor (GPCR) family that is an important drug target for asthma and COPD. Clinical studies coupled with biochemical data have identified a critical receptor variant, Thr164Ile, to have a reduced response to agonist-based therapy, although the molecular mechanism underlying this seemingly "non-deleterious" substitution is not clear. Here, we couple molecular dynamics simulations with network analysis and free-energy calculations to identify the molecular determinants underlying the differential drug response.
View Article and Find Full Text PDFOver the past decade, the vast amount of information generated through structural and biophysical studies of GPCRs has provided unprecedented mechanistic insight into the complex signalling behaviour of these receptors. With this recent information surge, it has also become increasingly apparent that in order to reproduce the various effects that lipids and membranes exert on the biological function for these allosteric receptors, in vitro studies of GPCRs need to be conducted under conditions that adequately approximate the native lipid bilayer environment. In the first part of this review, we assess some of the more general effects that a membrane environment exerts on lipid bilayer-embedded proteins such as GPCRs.
View Article and Find Full Text PDFG-protein-coupled receptors (GPCRs) are allosteric signaling proteins that transmit an extracellular stimulus across the cell membrane. Using F NMR and site-specific labelling, we investigate the response of the cytoplasmic region of transmembrane helices 6 and 7 of the β-adrenergic receptor to agonist stimulation and coupling to a G-protein-mimetic nanobody. Agonist binding shows the receptor in equilibrium between two inactive states and a pre-active form, increasingly populated with higher ligand efficacy.
View Article and Find Full Text PDFThe human β2-adrenergic receptor (β2AR) belongs to the G protein-coupled receptor (GPCR) family and due to its central role in bronchodilation, is an important drug target. The inter-individual variability in β2AR has been implicated in disease susceptibility and differential drug response. In this work, we identified nine potentially deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) using a consensus approach.
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