A Binding Site for CVN293 Reveals a Mechanism for Allosteric Control of THIK-1 K2P Channel Gating

CryoEM structures of human THIK-1 bound to CVN293 show the inhibitor binds deep in the inner cavity as a highly specific pore blocker.

• Why it matters: Microglial activation and neuroinflammation involve THIK-1, but the CVN293 binding site and inhibitory mechanism were unclear despite clinical trials for neurodegenerative disorders.
• What they did: The study solved cryoEM structures of human THIK-1 with CVN293 and C101248, then validated the binding site using functional and computational approaches.
• The result: The intracellular distal C-terminus does not block the pore; instead, the C-terminal domain allosterically controls channel activity via the Y-gate, integrating cellular signaling pathways.