6O00

apo-LRRC8A in MSP2N2 nanodisc constricted state

Summary for 6O00

• Entry DOI: 10.2210/pdb6o00/pdb
• Related: 6NZW 6NZZ
• EMDB information: 0562 0563 0564
• Descriptor: Volume-regulated anion channel subunit LRRC8A (1 entity in total)
• Functional Keywords: ion channel, volume-regulation, membrane protein
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 6
• Total formula weight: 571887.37

Authors

Kern, D.M.,Hite, R.K.,Brohawn, S.G. (deposition date: 2019-02-14, release date: 2019-02-27, Last modification date: 2025-05-28)

Primary citation

Kern, D.M.,Oh, S.,Hite, R.K.,Brohawn, S.G.
Cryo-EM structures of the DCPIB-inhibited volume-regulated anion channel LRRC8A in lipid nanodiscs.
Elife, 8:-, 2019

PubMed Abstract: 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 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.

PubMed: 30775971
DOI: 10.7554/eLife.42636

Experimental method

ELECTRON MICROSCOPY (4.18 Å)