Structural alignment of TRP channels to investigate selectivity and gating.

Abstract

Transient receptor potential (TRP) channels are polymodal sensors involved in responding to physiological changes such as chemical concentration and temperature. Widely expressed, TRP channels are drug targets for a variety of disorders, including chronic pain and inflammation, metabolic conditions, and cardiovascular diseases, though many channels lack specific modulators, limiting both treatment options and further study of individual channel properties. Divided into seven subfamilies based on their diverse extramembranous domains, all TRP channels share a highly conserved tetrameric transmembrane region that forms the cation-conducting pore, along with several well-characterized ligand binding sites. Understanding channel gating necessitates investigating the structural basis of how a modulating stimulus couples to the opening or closing of the conserved ion-conducting pore. A global structure-based alignment of 120 structures completed in 2020 gave insight into ion selectivity, open and closed channel pores, and ligand binding motif similarities within the conserved transmembrane region but found few structures with conducting pores. We have now completed an updated structural alignment of TRP channel transmembrane domains with 260 structures currently available and subsequent analysis supports previous work and provides new information on structural similarities and functions.