Biology subjects

Schioett, B.

Publications and source records attributed to Schioett, B..

2 recordsLinked to original sources

bioRxiv2026

Mechanistic Insights into Na+-dependent HCO3- Transport by NBCn2 (SLC4A10)

The 3D structure and mechanism of action are unknown for the integral plasma membrane transport protein Solute Carrier 4A10, which has been characterized functionally as an electroneutral Na+:HCO3- cotransporter. We used structure prediction and molecular dynamics simulations to study the binding of the transported ions to the Solute Carrier 4A10 protein and suggest a model of sequential binding of Na+ followed by HCO3- to the ion binding domain. The binding of HCO3- to the protein appears to depend absolutely on Na+ binding. Conversely, binding of HCO3- stabilizes the interaction between Na+ and its binding site. This allows the subsequent conformational changes of the Solute Carrier 4A10 protein and, thus, ion translocation. Measurements of intracellular pH and Na+ concentration revealed the dependence of Na+ on HCO3- transport. The study lays the necessary foundation for advanced analysis of ion translocation and the development of selective transport inhibitors of Solute Carrier 4A10 and other proteins of the protein family of HCO3- transporters.

biophysics↗

bioRxiv2021

Binding and activation of serotonergic G-protein coupled receptors by the multimodal antidepressant vortioxetine.

G-protein coupled receptors are important pharmacological targets. Despite substantial progress, important questions still remain concerning the details of activation: how can a ligand act as an agonist in one receptor, but as an antagonist in a homologous receptor, and how can agonists activate a receptor despite lacking polar functional groups able to interact with helix 5? Studying vortioxetine, an important multimodal antidepressant drug, may elucidate both questions. Herein, we present a thorough in silico analysis of vortioxetine binding to 5-HT1A, 5-HT1B, and 5-HT7 receptors and compare to available experimental data. We are able to rationalize the differential mode of action of vortioxetine at different receptors, but also, in the case of the 5-HT1A receptor, we observe the initial steps of activation suggesting that interaction with helix 5 does not necessarily require a hydrogen bond as previously suggested. The results extend our current understanding of agonist and antagonist action at GPCRs.

biophysics↗