Featured Research DBR

The Impact of Nanodiscs on Ion Channel Structure: Implications for Drug Design in Pain and Anesthesia

In a recent study published in Nature Communications on January 2, 2024, Vikram Dalal, PhD, Mark Arcario, MD, PhD, and colleagues investigated the structure of ligand-gated ion channels, which are the molecular targets of anesthetics.

Atomistic models of spMSP1D1ELIC (gray) equilibrated in a 9 nm and 11 nm MSP nanodisc. The MSP scaffolds are cyan and pink, and POPC is tan. For the top view, the ECD was removed to improve clarity of the TMD and MSP. 

Ion channels are usually reconstituted in nano-size particles called nanodiscs to determine atomic-resolution structures. Structures of ion channels are used to facilitate drug discovery targeting these proteins. In this study, researchers found that different nanodiscs produce distinct structures, challenging the prevailing assumption that all nanodiscs mimic a native cell membrane environment. The team proposes further exploration of nanodisc effects on other membrane proteins and advocates for a more nuanced consideration of nanodisc composition and size in structural biology studies.

Dalal is a postdoctoral research associate in Dr. Wayland Cheng’s lab, and Arcario is an instructor who recently received funding from an NIH K08 award. Cheng is an associate professor in the Division of Basic Research in the Department of Anesthesiology at Washington University School of Medicine in St. Louis. His research focuses on mechanisms of lipid regulation of ion channels, using electrophysiological techniques, photo-affinity labeling, native mass spectrometry, and single-particle cryo-EM.

“This study has major implications for drug discovery efforts that rely on using protein structure,” said Cheng. “The findings question the structural information we have, information that must be validated and supplemented with other techniques.”