Full and partial agonists of thromboxane prostanoid receptor unveil fine tuning of receptor superactive conformation and G protein activation.

The intrahelical salt bridge between E/D(3.49) and R(3.50) within the E/DRY motif on helix 3 (H3) and the interhelical hydrogen bonding between the E/DRY and residues on H6 are thought to be critical in stabilizing the class A G protein-coupled receptors in their inactive state.

Nonequilibrium activation of a G-protein-coupled receptor.

G-protein-coupled receptor activation is generally analyzed under equilibrium conditions. However, real-life receptor functions are often dependent on very short, transient stimuli that may not allow the achievement of a steady state. This is particularly true for synaptic receptors such as the α(2A)-adrenergic receptor (α(2A)-AR).

Light on the structure of thromboxane A₂receptor heterodimers.

The structure-based design of a mutant form of the thromboxane A(2) prostanoid receptor (TP) was instrumental in characterizing the structural determinants of the hetero-dimerization process of this G protein coupled receptor (GPCR). The results suggest that the hetero-dimeric complexes between the TPα and β isoforms are characterized by contacts between hydrophobic residues in helix 1 from both monomers. Functional characterization confirms that TPα-TPβ hetero-dimerization serves to regulate TPα function through agonist-induced internalization, with important implications in cardiovascular homeostasis.

Differential signaling of the endogenous agonists at the beta2-adrenergic receptor.

The concept of "functional selectivity" or "biased signaling" suggests that a ligand can have distinct efficacies with regard to different signaling pathways. We have investigated the question of whether biased signaling may be related to distinct agonist-induced conformational changes in receptors using the β(2)-adrenergic receptor (β(2)AR) and its two endogenous ligands epinephrine and norepinephrine as a model system. Agonist-induced conformational changes were determined in a fluorescently tagged β(2)AR FRET sensor.

Sensing G protein-coupled receptor activation.

G protein-coupled receptors (GPCRs) are the key elements of a highly regulated transduction machinery that generates different signaling outcomes to hormones and neurotransmitters. Until recently, it was assumed that diverse ligands of a given GPCR differ only in their ability to alter the balance between the OFF and the ON state of the receptor. However, it has now become evident that their activation mechanisms are more complex and that receptors presumably display distinguishable active conformational states, which are induced by different agonists and correlate to specific signaling outputs.

Superactive mutants of thromboxane prostanoid receptor: functional and computational analysis of an active form alternative to constitutively active mutants.

In class A GPCRs the E/DRY motif is critical for receptor activation and function. According to experimental and computational data, R3.50 forms a double salt bridge with the adjacent E/D3.