6Q6C

Pore-modulating toxins exploit inherent slow inactivation to block K+ channels

Summary for 6Q6C

• Entry DOI: 10.2210/pdb6q6c/pdb
• Descriptor: Kunitz-type conkunitzin-S1, PHOSPHATE ION, NITRATE ION, ... (5 entities in total)
• Functional Keywords: toxin
• Biological source: Conus striatus (Striated cone)
• Total number of polymer chains: 2
• Total formula weight: 14571.35

Authors

Karbat, I.,Gueta, H.,Fine, S.,Szanto, T.,Hamer-Rogotner, S.,Dym, O.,Frolow, F.,Gordon, D.,Panyi, G.,Gurevitz, M.,Reuveny, E. (deposition date: 2018-12-10, release date: 2019-08-21, Last modification date: 2024-11-13)

Primary citation

Karbat, I.,Altman-Gueta, H.,Fine, S.,Szanto, T.,Hamer-Rogotner, S.,Dym, O.,Frolow, F.,Gordon, D.,Panyi, G.,Gurevitz, M.,Reuveny, E.
Pore-modulating toxins exploit inherent slow inactivation to block K+channels.
Proc.Natl.Acad.Sci.USA, 116:18700-18709, 2019

PubMed Abstract: Voltage-dependent potassium channels (Ks) gate in response to changes in electrical membrane potential by coupling a voltage-sensing module with a K-selective pore. Animal toxins targeting Ks are classified as pore blockers, which physically plug the ion conduction pathway, or as gating modifiers, which disrupt voltage sensor movements. A third group of toxins blocks K conduction by an unknown mechanism via binding to the channel turrets. Here, we show that Conkunitzin-S1 (Cs1), a peptide toxin isolated from cone snail venom, binds at the turrets of K1.2 and targets a network of hydrogen bonds that govern water access to the peripheral cavities that surround the central pore. The resulting ectopic water flow triggers an asymmetric collapse of the pore by a process resembling that of inherent slow inactivation. Pore modulation by animal toxins exposes the peripheral cavity of K channels as a novel pharmacological target and provides a rational framework for drug design.

PubMed: 31444298
DOI: 10.1073/pnas.1908903116

Experimental method

X-RAY DIFFRACTION (1.3 Å)