8DJB

MthK-A90L mutant in closed state with 0 Ca2+

Summary for 8DJB

• Entry DOI: 10.2210/pdb8djb/pdb
• EMDB information: 27459
• Descriptor: Calcium-gated potassium channel MthK, POTASSIUM ION (2 entities in total)
• Functional Keywords: mthk, transport protein, ion channel
• Biological source: Methanothermobacter thermautotrophicus
• Total number of polymer chains: 8
• Total formula weight: 299225.03

Authors

Agarwal, S.,Nimigean, C.M. (deposition date: 2022-06-30, release date: 2023-07-05, Last modification date: 2024-01-03)

Primary citation

Fan, C.,Flood, E.,Sukomon, N.,Agarwal, S.,Allen, T.W.,Nimigean, C.M.
Calcium-gated potassium channel blockade via membrane-facing fenestrations.
Nat.Chem.Biol., 20:52-61, 2024

PubMed Abstract: Quaternary ammonium blockers were previously shown to bind in the pore to block both open and closed conformations of large-conductance calcium-activated potassium (BK and MthK) channels. Because blocker entry was assumed through the intracellular entryway (bundle crossing), closed-pore access suggested that the gate was not at the bundle crossing. Structures of closed MthK, a Methanobacterium thermoautotrophicum homolog of BK channels, revealed a tightly constricted intracellular gate, leading us to investigate the membrane-facing fenestrations as alternative pathways for blocker access directly from the membrane. Atomistic free energy simulations showed that intracellular blockers indeed access the pore through the fenestrations, and a mutant channel with narrower fenestrations displayed no closed-state TPeA block at concentrations that blocked the wild-type channel. Apo BK channels display similar fenestrations, suggesting that blockers may use them as access paths into closed channels. Thus, membrane fenestrations represent a non-canonical pathway for selective targeting of specific channel conformations, opening novel ways to selectively drug BK channels.

PubMed: 37653172
DOI: 10.1038/s41589-023-01406-2

Experimental method

ELECTRON MICROSCOPY (3.18 Å)