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疟原虫糖摄入的分子基础获解析
2020-02-10 09:54

瑞典斯德哥尔摩大学David Drew小组的一项最新研究揭示了疟原虫糖摄入的分子基础。相关论文于2020年1月29日在线发表于国际学术期刊《自然》。

研究人员表示,糖摄入机制的阐明需要对转运蛋白如何偶联糖结合和门控事件进行分子理解。哺乳动物葡萄糖转运蛋白(GLUT)是专门负责的蛋白,而疟疾寄生虫(恶性疟原虫)的己糖转运蛋白PfHT1具有与专门负责葡萄糖(GLUT3)和果糖(GLUT5)转运蛋白一样高效的能力。
 
为了建立疟疾寄生虫中糖选择性的分子基础,研究人员解析了与D-葡萄糖结合的PfHT1晶体结构,其分辨率为3.6埃。研究人员发现PfHT1中的糖结合位点与GLUT3和GLUT5结构的糖结合位点非常相似。尽管如此,为匹配GLUT糖结合位点而设计的工程化PfHT1突变并未改变糖的偏好。PfHT1中的细胞外底物门控螺旋TM7b处于完全封闭的构象中,这提供了糖结合和门控偶联的独特视角。研究人员发现,TM7b和TM1之间的极性接触(距离D-葡萄糖约15Å)与直接协调D-葡萄糖的残基一样对运输至关重要,这表明糖结合和门控之间存在很强的变构偶联。研究人员认为,PfHT1并非通过修饰其糖结合位点来实现底物多样性,而是通过进化底物门控动态来实现。
 
附:英文原文

Title: The molecular basis for sugar import in malaria parasites

Author: Abdul Aziz Qureshi, Albert Suades, Rei Matsuoka, Joseph Brock, Sarah E. McComas, Emmanuel Nji, Laura Orellana, Magnus Claesson, Lucie Delemotte, David Drew

Issue&Volume: 2020-01-29

Abstract: 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 specialists1, the hexose transporter from the malaria parasite Plasmodium falciparum PfHT12,3 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 . We found that the sugar-binding site in PfHT1 is very similar to those of the distantly related GLUT3 and GLUT5 structures4,5. 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 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.

DOI: 10.1038/s41586-020-1963-z

Source: https://www.nature.com/articles/s41586-020-1963-z

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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