Stockbridge Randy B, Kolmakova-Partensky Ludmila, Shane Tania, Koide Akiko, Koide Shohei, Miller Christopher, Newstead Simon
Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, Massachusetts 02454, USA.
Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois 60637, USA.
Nature. 2015 Sep 24;525(7570):548-51. doi: 10.1038/nature14981. Epub 2015 Sep 7.
To contend with hazards posed by environmental fluoride, microorganisms export this anion through F(-)-specific ion channels of the Fluc family. Since the recent discovery of Fluc channels, numerous idiosyncratic features of these proteins have been unearthed, including strong selectivity for F(-) over Cl(-) and dual-topology dimeric assembly. To understand the chemical basis for F(-) permeation and how the antiparallel subunits convene to form a F(-)-selective pore, here we solve the crystal structures of two bacterial Fluc homologues in complex with three different monobody inhibitors, with and without F(-) present, to a maximum resolution of 2.1 Å. The structures reveal a surprising 'double-barrelled' channel architecture in which two F(-) ion pathways span the membrane, and the dual-topology arrangement includes a centrally coordinated cation, most likely Na(+). F(-) selectivity is proposed to arise from the very narrow pores and an unusual anion coordination that exploits the quadrupolar edges of conserved phenylalanine rings.
为应对环境氟化物带来的危害，微生物通过Fluc家族的F(-)特异性离子通道输出这种阴离子。自最近发现Fluc通道以来，这些蛋白质的许多独特特征已被发掘出来，包括对F(-)的选择性远高于Cl(-)以及双拓扑二聚体组装。为了解F(-)通透的化学基础以及反平行亚基如何聚集形成F(-)选择性孔道，我们在此解析了两种细菌Fluc同源物与三种不同单克隆抗体抑制剂结合的晶体结构，分别在有和没有F(-)存在的情况下，最高分辨率达到2.1 Å。这些结构揭示了一种惊人的“双筒”通道结构，其中两条F(-)离子通道跨越膜，双拓扑排列包括一个中心配位阳离子，最有可能是Na(+)。F(-)选择性被认为源于非常狭窄的孔道以及利用保守苯丙氨酸环的四极边缘的异常阴离子配位。
