α1A-adrenoceptor inverse agonists and agonists modulate receptor signalling through a conformational selection mechanism

Abstract

G-Protein Coupled Receptors (GPCRs) transmit signals across the cell membrane via an allosteric network from the ligand-binding site to the G-protein binding site via a series of conserved microswitches. Crystal structures of GPCRs provide snapshots of inactive and active states, but poorly describe the conformational dynamics of the allosteric network that underlies GPCR activation. Here we analyse the correlation between ligand binding and receptor conformation of the α 1A -adrenoceptor, known for stimulating smooth muscle contraction in response to binding noradrenaline. NMR of 13 C ε H 3 -methionine labelled α 1A -adrenoreceptor mutants, each exhibiting differing signalling capacities, r..