LIGAND-INDUCED DOMAIN MOTION IN THE ACTIVATION MECHANISM OF A G-PROTEIN-COUPLED RECEPTOR

Rapidly accumulating information about the structures and functions of transmembrane proteins in the class of G-protein-coupled receptors is facilitating the exploration of molecular details in the processes of cellular signal transduction. We have described recently a 3-D molecular model of the transmembrane portion of the 5-HT2A type of receptor of the neurotransmitter serotonin (5-hydroxy-tryptamine; 5-HT), constructed from such convergent empirical and theoretical considerations, and have used it for a computational simulation of the mechanisms of ligand-induced receptor activation and signal transduction. The molecular dynamics (MD) simulation of the interaction between the receptor model and ligands of different pharmacological efficacies pointed to a set of specific conformational changes propagated from the ligand binding site to a distal region of the receptor that is essential for signal transduction. The ligand-induced changes were found to correlate well. with the known pharmacological properties, but it remained unclear how the binding of the small 5-HT2A receptor agonist molecules in the distal binding pocket could give rise to the specific conformational changes in a distant part of the receptor. As the MD simulations showed the secondary structure of the helical transmembrane domains of the receptor to be well maintained, and the conformational changes to involve mainly translations and rotations of the helices in the bundle relative to one another, an algorithm was developed to treat the ligand-induced conformational changes as rigid domain movements of transmembrane helices. The application of this algorithm to the analysis of MD trajectories for ligand-receptor complexes revealed a series of torques and inter-helix interaction forces that trigger the rotations responsible for domain motions. The detailed analysis explains the differences in the effects of pharmacologically distinct ligands observed from the MD simulations, and offers structural inferences that are verifiable with mutation experiments designed to diminish or enhance specific helix-ligand or helix-helix interactions.