Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140.
Proc Natl Acad Sci U S A. 2014 Apr 29;111(17):E1713-22. doi: 10.1073/pnas.1317573111. Epub 2014 Apr 14.
K(+) efflux through K(+) channels can be controlled by C-type inactivation, which is thought to arise from a conformational change near the channel's selectivity filter. Inactivation is modulated by ion binding near the selectivity filter; however, the molecular forces that initiate inactivation remain unclear. We probe these driving forces by electrophysiology and molecular simulation of MthK, a prototypical K(+) channel. Either Mg(2+) or Ca(2+) can reduce K(+) efflux through MthK channels. However, Ca(2+), but not Mg(2+), can enhance entry to the inactivated state. Molecular simulations illustrate that, in the MthK pore, Ca(2+) ions can partially dehydrate, enabling selective accessibility of Ca(2+) to a site at the entry to the selectivity filter. Ca(2+) binding at the site interacts with K(+) ions in the selectivity filter, facilitating a conformational change within the filter and subsequent inactivation. These results support an ionic mechanism that precedes changes in channel conformation to initiate inactivation.
通过 K(+) 通道的 K(+) 外流可以通过 C 型失活来控制，据认为这种失活是由于通道选择性过滤器附近的构象变化引起的。失活受选择性过滤器附近离子结合的调节；然而，引发失活的分子力仍不清楚。我们通过对 MthK（一种典型的 K(+) 通道）的电生理学和分子模拟来探究这些驱动力。Mg(2+) 或 Ca(2+) 都可以减少 MthK 通道中的 K(+) 外流。然而，Ca(2+)（而不是 Mg(2+)）可以增强进入失活状态的能力。分子模拟表明，在 MthK 孔中，Ca(2+) 离子可以部分去水合，从而使 Ca(2+) 选择性地进入选择性过滤器的入口。该位点的 Ca(2+) 结合与选择性过滤器中的 K(+) 离子相互作用，促进过滤器内的构象变化和随后的失活。这些结果支持了一种离子机制，该机制先于通道构象变化引发失活。
