Crystal structure of the sodium-potassium pump (Na+, K+-ATPase) with bound potassium and ouabain
Crystal structure of the sodium-potassium pump (Na+, K+-ATPase) with bound potassium and ouabain
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DOI：
10.1073/pnas.0907054106
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发表时间：
2009-08-18
影响因子：
11.1
通讯作者：
Toyoshima, Chikashi
中科院分区：
文献类型：
--
作者：
Ogawa, Haruo;Shinoda, Takehiro;Toyoshima, Chikashi
钠-钾泵(Na+，K+-ATPase)负责建立跨质膜的Na+和K+浓度梯度，因此在产生动作电位等方面起着重要作用。治疗充血性心力衰竭已有两百多年的历史，心苷类药物是这种ATPase的有效抑制剂。本文描述了一种结合哇巴因的Na~+，K~+-ATPase的晶体结构，其分辨率为2.8埃，类似于E_2中心点2K(+)中心点PI。哇巴因被深深插入跨膜区，内酯环非常接近结合的K+，这与以前的模型形成了鲜明的对比。由于哇巴因与K+的拮抗作用，该结构呈现低亲和力的哇巴因结合状态。然而，大多数在高亲和力状态下获得的突变数据很容易用目前的晶体结构来解释，这表明哇巴因的结合位置基本上是相同的。根据高亲和力状态的同源模型，结合腔的关闭赋予了高亲和力。
The sodium-potassium pump (Na+, K+-ATPase) is responsible for establishing Na+ and K+ concentration gradients across the plasma membrane and therefore plays an essential role in, for instance, generating action potentials. Cardiac glycosides, prescribed for congestive heart failure for more than 2 centuries, are efficient inhibitors of this ATPase. Here we describe a crystal structure of Na+, K+-ATPase with bound ouabain, a representative cardiac glycoside, at 2.8 angstrom resolution in a state analogous to E2 center dot 2K(+)center dot Pi. Ouabain is deeply inserted into the transmembrane domain with the lactone ring very close to the bound K+, in marked contrast to previous models. Due to antagonism between ouabain and K+, the structure represents a low-affinity ouabain-bound state. Yet, most of the mutagenesis data obtained with the high-affinity state are readily explained by the present crystal structure, indicating that the binding site for ouabain is essentially the same. According to a homology model for the high affinity state, it is a closure of the binding cavity that confers a high affinity.