11DF
Human Slo1-Iberiotoxin complex under divalent chelated condition - gating ring masked map
Summary for 11DF
| Entry DOI | 10.2210/pdb11df/pdb |
| EMDB information | 75633 |
| Descriptor | Calcium-activated potassium channel subunit alpha-1, Potassium channel toxin alpha-KTx 1.3, POTASSIUM ION, ... (7 entities in total) |
| Functional Keywords | bk, human bk, hslo1, iberiotoxin, ion channel, membrane protein, membrane protein-toxin complex, membrane protein/toxin |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 5 |
| Total formula weight | 558811.51 |
| Authors | |
| Primary citation | Kallure, G.S.,Pal, K.,Prather, G.W.,Chowdhury, S. Structural underpinnings of human Slo1 inhibition by scorpion and fungal toxins. Proc.Natl.Acad.Sci.USA, 123:e2606537123-e2606537123, 2026 Cited by PubMed Abstract: Slo1 channels regulate key electrochemical signaling events in a variety of excitable and nonexcitable cells. Here, we have investigated the mechanisms by which distinct small molecules inhibit human Slo1 (hSlo1) channel activity using single-particle cryo-EM, liposome flux, and toxin-binding assays. We find that unlike classical permeation blockers like scorpion toxins, indole diterpene (ID) class of fungal mycotoxins, paxilline and penitrem A, are ensconced in a binding pocket, deep within the putatively closed hSlo1 pore and sterically restrict its opening. Binding of paxilline to its gating inhibition site dramatically slows dissociation of a fluorescent charybdotoxin derivative, via an allosteric mechanism that likely involves a key residue on the S5 helix (W246). Although four paxilline molecules may concurrently engage the hSlo1 pore, binding of <4 molecules is sufficient for efficacious inhibition of channel opening but inefficient at arresting toxin dissociation. We also find evidence that under divalent and ID free conditions, the ID binding pocket of hSlo1 is occluded by lipids that extend into the hSlo1 pore lumen through interhelical crevices that become constricted in the divalent bound open state. These lipids may not only competitively regulate ID binding but also tune the energetics of channel gating, sterically or by altering the hydration state of the pore vestibule. Our study provides a framework to understand fundamental Slo1 gating mechanisms and aid future developments of therapeutically beneficial small molecule Slo1 inhibitors. PubMed: 42735318DOI: 10.1073/pnas.2606537123 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.1 Å) |
Structure validation
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