CodB is a cytosine transporter from the Nucleobase-Cation-Symport-1 (NCS1) transporter family, a member of the widespread LeuT superfamily. Previous experiments with the nosocomial pathogen Pseudomonas aeruginosa have shown CodB as also important for the uptake of 5-fluorocytosine, which has been suggested as a novel drug to combat antimicrobial resistance by suppressing virulence. Here we solve the crystal structure of CodB from Proteus vulgaris, at 2.4 Å resolution in complex with cytosine. We show that CodB carries out the sodium-dependent uptake of cytosine and can bind 5-fluorocytosine. Comparison of the substrate-bound structures of CodB and the hydantoin transporter Mhp1, the only other NCS1 family member for which the structure is known, highlight the importance of the hydrogen bonds that the substrates make with the main chain at the breakpoint in the discontinuous helix, TM6. In contrast to other LeuT superfamily members, neither CodB nor Mhp1 makes specific interactions with residues on TM1. Comparison of the structures provides insight into the intricate mechanisms of how these proteins transport substrates across the plasma membrane.

中文翻译：

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胞嘧啶转运蛋白 CodB 的结构提供了对核碱基阳离子转运体 1 机制的深入了解

CodB 是来自 Nucleobase-Cation-Symport-1 (NCS1) 转运蛋白家族的胞嘧啶转运蛋白，该家族是广泛存在的 LeuT 超家族的成员。先前对医院病原体铜绿假单胞菌的实验表明，CodB 对于 5-氟胞嘧啶的摄取也很重要，这已被认为是一种通过抑制毒力来对抗抗菌素耐药性的新药。在这里我们解决了来自普通变形杆菌的 CodB 的晶体结构，以 2.4 Å 分辨率与胞嘧啶复合。我们表明，CodB 对胞嘧啶进行钠依赖性摄取，并且可以结合 5-氟胞嘧啶。比较 CodB 和乙内酰脲转运蛋白 Mhp1 的底物结合结构，这是已知结构的唯一其他 NCS1 家族成员，突出了底物与主链在不连续螺旋断点处形成的氢键的重要性，TM6。与其他 LeuT 超家族成员相比，CodB 和 Mhp1 都不会与 TM1 上的残基发生特定的相互作用。结构的比较提供了对这些蛋白质如何跨质膜转运底物的复杂机制的深入了解。