9T5Q
LRR domain Structure of LRRC8A in complex with synthetic nanobody Sb4
Summary for 9T5Q
| Entry DOI | 10.2210/pdb9t5q/pdb |
| Descriptor | Volume-regulated anion channel subunit LRRC8A, Sb4 (3 entities in total) |
| Functional Keywords | cytosolic domain of lrrc8a in complex with sb4, cytosolic protein |
| Biological source | Mus musculus (house mouse) More |
| Total number of polymer chains | 4 |
| Total formula weight | 123924.55 |
| Authors | Lehmann, E.F.,Deneka, D.,Stierli, F.,Rutz, S.,Dutzler, R. (deposition date: 2025-11-05, release date: 2026-09-02, Last modification date: 2026-09-30) |
| Primary citation | Lehmann, E.F.,Stierli, F.,Rutz, S.,Deneka, D.,Dutzler, R. Structures of the volume-regulated anion channel LRRC8A/D in activating and inhibiting conditions. Nat Commun, 17:-, 2026 Cited by PubMed Abstract: Volume-regulated anion channels, which are activated in response to hypotonicity, are heteromers composed of LRRC8 family members. They consist of the obligatory subunit LRRC8A and at least another paralog that determines their substrate preference. Here we investigate heteromeric assemblies composed of LRRC8A and D subunits, the latter of which confer permeability to amino acids, osmolytes and anti-cancer drugs. Using patch-clamp electrophysiology, we show that LRRC8A/D channels are reversibly activated by cell swelling and that their response is modulated by sybodies targeting the A subunits, which either potentiate or repress channel activity. Structures of the LRRC8A/D channel in complex with the inhibitory sybody Sb1 define the channel stoichiometry of four A and two D subunits, with Sb1 stabilizing the A subunits in a similar closed channel conformation as found in homomeric LRRC8A assemblies. In LRRC8A/D heteromers, the two D subunits weaken the arrangement of A subunits and thus enhance the activation properties of the channel. This channel conformation is strongly perturbed upon binding of the potentiating sybody Sb4, which disrupts the packing of the cytoplasmic domains linking their mobility to pore opening. PubMed: 42754598DOI: 10.1038/s41467-026-77508-x PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.6 Å) |
Structure validation
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