12 April 2019

Protein Analysis Group publishes in prestigious Nature journal

Publication

Work lead by Prof. Kasper Rand (Protein Analysis Group, Department of Pharmacy) and Prof. Claus Løland (Department of Neuroscience) has been published in the journal Nature Communications on April 11, 2019.

Claus Løland, Anne Kathrine Nielsen, Ingvar Rúnar Möller and Kasper Rand

The paper, entitled Conformational dynamics of the human serotonin transporter during substrate and drug binding, is the result of a long-standing collaboration between the Protein Analysis Group (lead by Prof. Kasper Rand) and the Molecular Neuropharmacology Group of Prof. Claus Løland of the Department of Neuroscience.

The human serotonin transporter (SERT), a key member of the larger neurotransmitter:sodium symporter (NSS) family, is an integral membrane protein that is responsible for the termination of neuronal signaling by re-uptake of serotonin (5-HT) into the presynaptic neuron. Despite a critical role in biology and as the major target for antidepressant drugs, insufficient knowledge is available concerning the changes occurring in the structure of SERT during substrate transport and drug binding.

In the work, the researchers use the sensitive analytical method, hydrogen-deuterium exchange mass spectrometry, with which the Protein Analysis Group has unique expertise, to provide the first unperturbed global view of the conformational dynamics of wild-type human SERT in solution. They further show how such dynamics are modulated by binding of both the biologically relevant substrate and ions (5-HT, Na+, K+), and three ligands of pharmaceutical interest.

“By spatially-resolving regions that change conformation in different functional states of SERT and/or are important for ion, substrate and drug binding, the results provide a framework for an improved understanding of the alternating access mechanism that governs the function of human SERT. Considering that the transport mechanism and drug binding for SERT is dictated by its higher-order structure, we envisage that other human transporters bearing the conserved NSS fold may operate via a similar mechanism of action.” says Prof. Rand. He further elaborates: “From a method view-point, the work highlights the applicability of HDX-MS to study the dynamic structure-function relationships and drug binding of such complex human membrane transport proteins”.

The project started in 2014 thanks to an FP1 grant from Danmarks Frie Forskning to Kasper Rand, allowing the recruitment of PhD student Ingvar Møller, who has worked on the project throughout his PhD and as a postdoc in the Protein Analysis Group.

Find out more about the Protein Analysis Group and the Molecular Neuropharmacology Group.