Serotonin receptors (5-HT3AR) play a crucial role in regulating gut movement, and are the principal target of setrons, a class of high-affinity competitive antagonists, used in the management of nausea and vomiting associated with radiation and chemotherapies. Structural insights into setron-binding poses and their inhibitory mechanisms are just beginning to emerge. Here, we present high-resolution cryo-EM structures of full-length 5-HT3AR in complex with palonosetron, ondansetron, and alosetron. Molecular dynamic simulations of these structures embedded in a fully-hydrated lipid environment assessed the stability of ligand-binding poses and drug-target interactions over time. Together with simulation results of apo- and serotonin-bound 5-HT3AR, the study reveals a distinct interaction fingerprint between the various setrons and binding-pocket residues that may underlie their diverse affinities. In addition, varying degrees of conformational change in the setron-5-HT3AR structures, throughout the channel and particularly along the channel activation pathway, suggests a novel mechanism of competitive inhibition.
- Sudha Chakrapani
- Sandip Basak
- Arvind Kumar
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Cynthia M Czajkowski, University of Wisconsin, Madison, United States
- Received: April 15, 2020
- Accepted: October 15, 2020
- Accepted Manuscript published: October 16, 2020 (version 1)
© 2020, Basak et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Downloads (link to download the article as PDF)
Download citations (links to download the citations from this article in formats compatible with various reference manager tools)
Open citations (links to open the citations from this article in various online reference manager services)
Research careers are typically envisioned as a single path in which researchers start being one of a large number of researchers working under the guidance of one or more experienced scientists and, if they are successful, end with the individual leading their own research group and training future generations of scientists. Here we study the author contribution statements of published research papers in order to explore possible biases and disparities in career trajectories in science. We used Bayesian networks to train a prediction model based on a dataset of 70,694 publications from PLoS journals, which included 347,136 distinct authors and their associated contribution statements. This model was used to predict the contributions of 222,925 authors in 6,236,239 publications, and to apply a robust archetypal analysis to profile scientists across four career stages: junior, early-career, mid-career and late-career. All three of the archetypes we found - leader, specialized, and supporting - were encountered for early-career and mid-career researchers. Junior researchers displayed only two archetypes (specialized, and supporting), as did late-career researchers (leader and supporting). Scientists assigned to the leader and specialized archetypes tended to have longer careers than those assigned to the supporting archetype. We also observed consistent gender bias at all stages: the majority of male scientists belonged to the leader archetype, while the larger proportion of women belonged to the specialized archetype, especially for early-career and mid-career researchers.
Glutamate delta (GluD) receptors belong to the ionotropic glutamate receptor family, yet they don't bind glutamate and are considered orphan. Progress in defining the ion channel function of GluDs in neurons has been hindered by a lack of pharmacological tools. Here we used a chemo-genetic approach to engineer specific and photo-reversible pharmacology in GluD2 receptor. We incorporated a cysteine mutation in the cavity located above the putative ion channel pore, for site-specific conjugation with a photoswitchable pore blocker. In the constitutively-open GluD2 Lurcher mutant, current could be rapidly and reversibly decreased with light. We then transposed the cysteine mutation to the native receptor, to demonstrate with high pharmacological specificity that metabotropic glutamate receptor signaling triggers opening of GluD2. Our results assess the functional relevance of GluD2 ion channel and introduce an optogenetic tool that will provide a novel and powerful means for probing GluD2 ionotropic contribution to neuronal physiology.