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Title | Cryo-EM structures of the DCPIB-inhibited volume-regulated anion channel LRRC8A in lipid nanodiscs. |
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Journal, issue, pages | Elife, Vol. 8, Year 2019 |
Publish date | Feb 18, 2019 |
Authors | David M Kern / SeCheol Oh / Richard K Hite / Stephen G Brohawn / |
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 ...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. |
External links | Elife / PubMed:30775971 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.21 - 4.18 Å |
Structure data | EMDB-0562, PDB-6nzw: |
Chemicals | ChemComp-POV: ChemComp-L9Y: |
Source |
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Keywords | MEMBRANE PROTEIN / Ion channel / volume-regulation |