Send to

Choose Destination

See 1 citation found by title matching your search:

Elife. 2019 Feb 18;8. pii: e42636. doi: 10.7554/eLife.42636.

Cryo-EM structures of the DCPIB-inhibited volume-regulated anion channel LRRC8A in lipid nanodiscs.

Author information

Department of Molecular & Cell Biology, University of California, Berkeley, Berkeley, United States.
Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, United States.
Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States.


Hypoosmotic conditions activate volume-regulated anion channels in vertebrate cells. These channels are formed by leucine-rich repeat-containing protein 8 (LRRC8) family members and contain LRRC8A in homo- or hetero-hexameric assemblies. Here, we present single-particle cryo-electron microscopy structures of Mus musculus LRRC8A in complex with the inhibitor DCPIB reconstituted in lipid nanodiscs. DCPIB plugs the channel like a cork in a bottle - binding in the extracellular selectivity filter and sterically occluding ion conduction. Constricted and expanded structures reveal coupled dilation of cytoplasmic LRRs and the channel pore, suggesting a mechanism for channel gating by internal stimuli. Conformational and symmetry differences between LRRC8A structures determined in detergent micelles and lipid bilayers related to reorganization of intersubunit lipid binding sites demonstrate a critical role for the membrane in determining channel structure. These results provide insight into LRRC8 gating and inhibition and the role of lipids in the structure of an ionic-strength sensing ion channel.


LRRC8; VRAC; cryo-EM; ion channel; molecular biophysics; mouse; neuroscience; structural biology; volume regulation

Supplemental Content

Full text links

Icon for eLife Sciences Publications, Ltd Icon for PubMed Central
Loading ...
Support Center