Xu Yanping, Shin Hyeon-Gyu, Szép Szilvia, Lu Zhe
Department of Physiology, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Nat Struct Mol Biol. 2009 Dec;16(12):1252-8. doi: 10.1038/nsmb.1717. Epub 2009 Nov 15.
Strong voltage sensitivity of inward-rectifier K(+) (Kir) channels has been hypothesized to arise primarily from an intracellular blocker displacing up to five K(+) ions from the wide, intracellular part of the ion conduction pore outwardly across the narrow ion-selectivity filter. The validity of this hypothesis depends on two assumptions: (i) that five ion sites are located intracellular to the filter and (ii) that the blocker can force essentially unidirectional K(+) movement in a pore region generally wider than the combined dimensions of the blocker plus a K(+) ion. Here we present a crystal structure of the cytoplasmic portion of a Kir channel with five ions bound and demonstrate that a constriction near the intracellular end of the pore, acting as a gasket, prevents K(+) ions from bypassing the blocker. This heretofore unrecognized 'gasket' ensures that the blocker can effectively displace K(+) ions across the selectivity filter to generate exceedingly strong voltage sensitivity.
内向整流钾离子（Kir）通道的强电压敏感性被认为主要源于一种细胞内阻滞剂将多达五个钾离子从离子传导孔宽阔的细胞内部分向外推过狭窄的离子选择性过滤器。这一假设的有效性取决于两个假设：（i）五个离子位点位于过滤器的细胞内；（ii）阻滞剂能够在一个通常比阻滞剂加上一个钾离子的组合尺寸更宽的孔区域中迫使钾离子基本单向移动。在这里，我们展示了一个结合了五个离子的Kir通道细胞质部分的晶体结构，并证明孔细胞内端附近的一个狭窄部分作为垫圈，可防止钾离子绕过阻滞剂。这种此前未被认识到的“垫圈”确保了阻滞剂能够有效地将钾离子推过选择性过滤器，从而产生极强的电压敏感性。
