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 molecu lar model of the transmembrane portion of the 5-HT2A type of receptor of the neurotransmitter serotonin (5-hydroxy-tryptamine; 5-HT), constr ucted from such convergent empirical and theoretical considerations, a nd have used it for a computational simulation of the mechanisms of li gand-induced receptor activation and signal transduction. The molecula r dynamics (MD) simulation of the interaction between the receptor mod el and ligands of different pharmacological efficacies pointed to a se t of specific conformational changes propagated from the ligand bindin g 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 h ow the binding of the small 5-HT2A receptor agonist molecules in the d istal binding pocket could give rise to the specific conformational ch anges in a distant part of the receptor. As the MD simulations showed the secondary structure of the helical transmembrane domains of the re ceptor to be well maintained, and the conformational changes to involv e mainly translations and rotations of the helices in the bundle relat ive to one another, an algorithm was developed to treat the ligand-ind uced conformational changes as rigid domain movements of transmembrane helices. The application of this algorithm to the analysis of MD traj ectories for ligand-receptor complexes revealed a series of torques an d inter-helix interaction forces that trigger the rotations responsibl e for domain motions. The detailed analysis explains the differences i n the effects of pharmacologically distinct ligands observed from the MD simulations, and offers structural inferences that are verifiable w ith mutation experiments designed to diminish or enhance specific heli x-ligand or helix-helix interactions.