Role of primary and secondary protein structure in neurotransmitter receptor activation mechanisms.
Review
Overview
abstract
A proton transfer triggered by a ligand interacting with the receptor had been suggested as the initial step in the activation of a receptor for the neurotransmitter serotonin (5-hydroxy-tryptamine; 5-HT). To evaluate the role of the receptor macromolecule in modulating the primary molecular event in ligand-mediated activation, the process of proton transfer was analysed in the environment of a protein model for the 5-HT receptor. In the absence of a detailed receptor structure, the enzyme actinidin was chosen as the model for the receptor based on criteria obtained from structure-activity considerations on the ligands. The first simulation of a mechanism for receptor activation was performed on this model using methods of theoretical chemistry to study the effect of specific structural elements. The premise is that the role of the elements of secondary structure of soluble proteins (e.g. actinidin) in determining structure-function relations in these macromolecules is maintained when these elements are part of membrane-bound receptor proteins. Results from the calculations of the effects of the six alpha helices of actinidin on the proton transfer process from the imidazolium side chain of His 162 to the thiol side chain of Cys 25 in the protein show that the helices contribute in different ways to modulate the energy of proton transfer. The largest helix, A1, opposes the proton transfer through the effect of the helix dipole. The charged residues (primary structure) in helix A3 favor the proton transfer, and mask the effect of its helix dipole (secondary structure) which opposes the transfer. The direction of the proton transfer simulated for the activation mechanism is opposite to that assumed in the catalytic process of the thiol protease, and the entire protein environment opposes the transfer. This supports the specific role of the ligand in triggering the proton transfer as a response to its binding.
