The molecular basis for sugar import in malaria parasites
The molecular basis for sugar import in malaria parasites
复制标题
疟原虫糖输入的分子基础
DOI：
10.1038/s41586-020-1963-z
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发表时间：
2020-01-29
期刊：
影响因子：
64.8
通讯作者：
Drew, David
中科院分区：
文献类型：
--
作者：
Qureshi, Abdul Aziz;Suades, Albert;Drew, David
阐明糖输入的机制需要对转运蛋白如何偶联糖结合和门控事件的分子理解。尽管哺乳动物葡萄糖转运蛋白（GLUT）是专家（1），但来自疟疾寄生虫恶性疟原虫PfHT 1（2，3）的己糖转运蛋白已经获得了与专用葡萄糖（GLUT 3）和果糖（GLUT 5）转运蛋白一样有效地转运葡萄糖和果糖的能力。在这里，为了建立疟疾寄生虫中糖混杂的分子基础，我们以3.6埃的分辨率确定了PfHT 1与d-葡萄糖复合物的晶体结构。我们发现PfHT 1中的糖结合位点与远亲GLUT 3和GLUT 5结构的糖结合位点非常相似（4，5）。然而，工程PfHT 1突变匹配GLUT糖结合位点没有改变糖的偏好。PfHT 1中的细胞外底物门控螺旋TM 7 b位于完全封闭的构象中，为糖结合和门控如何耦合提供了独特的一瞥。我们确定TM 7 b和TM 1之间的极性接触（距离d-葡萄糖约15埃）与直接协调d-葡萄糖的残基一样对转运至关重要，这表明糖结合和门控之间存在强烈的变构偶联。我们的结论是，PfHT 1已实现基板混杂不通过修改其糖结合位点，而是通过不断发展的基板门控dynamics.Crystal结构的恶性疟原虫己糖转运蛋白PfHT 1揭示了其能够有效地运输多种类型的糖作为专用的哺乳动物葡萄糖和果糖转运蛋白的分子基础。
Elucidating the mechanism of sugar import requires a molecular understanding of how transporters couple sugar binding and gating events. Whereas mammalian glucose transporters (GLUTs) are specialists(1), the hexose transporter from the malaria parasite Plasmodium falciparum PfHT1(2,3) has acquired the ability to transport both glucose and fructose sugars as efficiently as the dedicated glucose (GLUT3) and fructose (GLUT5) transporters. Here, to establish the molecular basis of sugar promiscuity in malaria parasites, we determined the crystal structure of PfHT1 in complex with d-glucose at a resolution of 3.6 angstrom. We found that the sugar-binding site in PfHT1 is very similar to those of the distantly related GLUT3 and GLUT5 structures(4,5). Nevertheless, engineered PfHT1 mutations made to match GLUT sugar-binding sites did not shift sugar preferences. The extracellular substrate-gating helix TM7b in PfHT1 was positioned in a fully occluded conformation, providing a unique glimpse into how sugar binding and gating are coupled. We determined that polar contacts between TM7b and TM1 (located about 15 angstrom from d-glucose) are just as critical for transport as the residues that directly coordinate d-glucose, which demonstrates a strong allosteric coupling between sugar binding and gating. We conclude that PfHT1 has achieved substrate promiscuity not by modifying its sugar-binding site, but instead by evolving substrate-gating dynamics.Crystal structure of the Plasmodium falciparum hexose transporter PfHT1 reveals the molecular basis of its ability to transport multiple types of sugar as efficiently as the dedicated mammalian glucose and fructose transporters.