Structural insights into the nucleotide base specificity of P2X receptors.
Structural insights into the nucleotide base specificity of P2X receptors.
复制标题
P2X 受体核苷酸碱基特异性的结构见解。
DOI：
10.1038/srep45208
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发表时间：
2017-03-23
影响因子：
4.6
通讯作者：
Nureki O
中科院分区：
文献类型：
--
作者：
Kasuya G;Fujiwara Y;Tsukamoto H;Morinaga S;Ryu S;Touhara K;Ishitani R;Furutani Y;Hattori M;Nureki O
P2X受体是三聚体ATP门控阳离子通道，参与从肌肉收缩到伤害感受等多种生理过程。尽管最近确定了与ATP结合的P2X受体的结构，但核苷酸碱基特异性的分子机制仍然难以捉摸。在此，我们展示了斑马鱼P2X4与一种弱亲和力激动剂CTP结合的晶体结构，以及基于结构的电生理和光谱分析。与CTP结合的结构揭示了在胞嘧啶碱基和激动剂结合位点的碱性残基侧链之间存在一个氢键，该氢键介导了对CTP较弱但显著的亲和力。胞嘧啶碱基还被两个主链原子识别，就像在与ATP结合的结构中一样，但它们的键长在与CTP结合的结构中似乎延长了，这也可能导致对CTP的亲和力比对ATP弱。这项工作为P2X受体的核苷酸碱基特异性提供了结构上的见解。
P2X receptors are trimeric ATP-gated cation channels involved in diverse physiological processes, ranging from muscle contraction to nociception. Despite the recent structure determination of the ATP-bound P2X receptors, the molecular mechanism of the nucleotide base specificity has remained elusive. Here, we present the crystal structure of zebrafish P2X4 in complex with a weak affinity agonist, CTP, together with structure-based electrophysiological and spectroscopic analyses. The CTP-bound structure revealed a hydrogen bond, between the cytosine base and the side chain of the basic residue in the agonist binding site, which mediates the weak but significant affinity for CTP. The cytosine base is further recognized by two main chain atoms, as in the ATP-bound structure, but their bond lengths seem to be extended in the CTP-bound structure, also possibly contributing to the weaker affinity for CTP over ATP. This work provides the structural insights for the nucleotide base specificity of P2X receptors.