Domene Carmen, Klein Michael L, Branduardi Davide, Gervasio Francesco L, Parrinello Michele
Physical and Theoretical Chemistry Laboratory, Department of Chemistry, University of Oxford, South Parks Road, Oxford OX1 3QZ, UK.
J Am Chem Soc. 2008 Jul 23;130(29):9474-80. doi: 10.1021/ja801792g. Epub 2008 Jun 28.
The translocation of ions and water across cell membranes is a prerequisite for many of life's processes. K(+) channels are a diverse family of integral membrane proteins through which K(+) can pass selectively. There is an ongoing debate about the nature of conformational changes associated with the opening and closing and conductive and nonconductive states of potassium (K(+)) channels. These changes depend on the membrane potential, the K(+) concentration gradient, and large scale motions of transmembrane helices and associated residues. Experiments also suggest that local structural changes in the selectivity filter may act as the dominant gate referred to as C-type inactivation. Herein we present an extensive computational study on KirBac, which supports the existence of a physical gate or constriction in the selectivity filter (SF) of K(+) channels. Our computations identify a new selectivity filter structure, which is likely associated with C-type inactivation. Specifically, the four peptide chains that comprise the filter adopt an unusual structure in which their dihedrals alternate between left- and right-handed Ramachandran angles, which also justifies the need for conservation of glycine in the K(+) selectivity filter, since it is the only residue able to play this bifunctional role.
离子和水跨细胞膜的转运是许多生命过程的先决条件。钾离子通道是一类多样的整合膜蛋白家族，钾离子可通过这些通道进行选择性通透。关于与钾（K⁺）通道的开放、关闭以及导通和非导通状态相关的构象变化的本质，目前仍存在争议。这些变化取决于膜电位、钾离子浓度梯度以及跨膜螺旋和相关残基的大规模运动。实验还表明，选择性过滤器中的局部结构变化可能充当被称为C型失活的主要门控。在此，我们展示了一项关于KirBac的广泛计算研究，该研究支持钾离子通道的选择性过滤器（SF）中存在物理门控或缩窄。我们的计算确定了一种新的选择性过滤器结构，它可能与C型失活有关。具体而言，构成过滤器的四条肽链采用了一种不寻常的结构，其中它们的二面角在左手和右手拉氏角之间交替，这也解释了在钾离子选择性过滤器中保守甘氨酸的必要性，因为它是唯一能够发挥这种双功能作用的残基。
