Illuminating the Molecular Machinery of the Serotonin Transporter
The serotonin transporter (SERT) regulates neurotransmission in the brain by catalyzing the reuptake of serotonin molecules from the synaptic cleft. Reuptake is critical for normal serotonergic signaling throughout the body, with implications for behavior, cognition, sleep, and appetite. As such, neurotransmitter reuptake transporters like SERT are major drug targets for antidepressants and other therapeutic molecules for the treatment of various psychiatric and neurodegenerative disorders. Recent advancements in cryogenic electron microscopy have uncovered the structural basis of inhibitor binding to these transporters. However, as with many proteins, these transporters undergo large structural rearrangements, and as such, the dynamics and transitions between conformational states cannot be solely determined from static structures.
The cover image for the March 1 issue of Biophysical Journal is an artistic rendering of the molecular machinery involved in serotonin import by SERT (shown as a pink cartoon). Proteins are nature’s molecular machines and are tightly regulated to ensure proper function. Specifically, the import of serotonin is facilitated by the favorable binding and co-transport of sodium ions (depicted as purple spheres). Additionally, proper SERT function is dependent on chloride (green spheres) and potassium ions. How these ions are coupled to substrate transport and mediate the necessary structural rearrangements of this important molecular machine remains elusive.
In our computational study, we used adaptive sampling and Markov state modeling to provide an atomistic view of the serotonin import process. In doing so, our simulations illuminated various molecular processes involved in substrate import, including serotonin recognition into the allosteric and central binding site, the binding of sodium and chloride ions, the co-transport of a sodium ion, and conformational transitions to allow for substrate release into the cell. Our computational approach demonstrates the power of molecular simulations to obtain a comprehensive view of intricate protein dynamics at fully atomistic resolution.
– Matthew C. Chan, Balaji Selvam, Heather J. Young, Erik Procko, and Diwakar Shukla
Read the full article on https://www.cell.com/biophysj/fulltext/S0006-3495(22)00074-1