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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Binding Of An Octylglucoside Detergent Molecule In The Second Substrate (s2) Site Of Leut Establishes An Inhibitor-bound Conformation
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Binding Of An Octylglucoside Detergent Molecule In The Second Substrate (s2) Site Of Leut Establishes An Inhibitor-bound Conformation

机译：Leut的第二个底物（s2）位点中的辛基葡萄糖苷洗涤剂分子的结合建立了抑制剂结合的构象

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摘要

The first crystal structure of the neurotransmitter/sodium sym-porter homolog LeuT revealed an occluded binding pocket containing leucine and 2 Na~+; later structures showed tricyclic anti-depressants (TCAs) in an extracellular vestibule ≈ 11 A above the bound leucine and 2 Na~+. We recently found this region to be a second binding (S2) site and that binding of substrate to this site triggers Na~+-coupled substrate symport. Here, we show a profound inhibitory effect of n-octyl-β-D-glucopyranoside (OG), the detergent used for LeuT crystallization, on substrate binding to the S2 site. In parallel, we determined at 2.8 A the structure of LeuT-E290S, a mutant that, like LeuT-WT, binds 2 substrate molecules. This structure was similar to that of WT and clearly revealed an OG molecule in the S2 site. We also observed electron density at the S2 site in LeuT-WT crystals, and this also was accounted for by an OG molecule in that site. Computational analyses, based on the available crystal structures of LeuT, indicated the nature of structural arrangements in the extracellular region of LeuT that differentiate the actions of substrates from inhibitors bound in the S2 site. We conclude that the current LeuT crystal structures, all of which have been solved in OG, represent functionally blocked forms of the transporter, whereas a substrate bound in the S2 site will promote a different state that is essential for Na~+-coupled symport.
机译：神经递质/钠共转运蛋白同系物LeuT的第一个晶体结构揭示了一个封闭的包含亮氨酸和2 Na〜+的结合口袋。后来的结构在结合的亮氨酸和2 Na〜+上方的细胞外前庭中显示出三环抗抑郁药（TCA）≈11A。最近，我们发现该区域是第二个结合（S2）位点，并且底物与该位点的结合触发了Na +偶联的底物共生。在这里，我们显示了用于LeuT结晶的去污剂正辛基-β-D-吡喃葡萄糖苷（OG）对与S2位点结合的底物具有深远的抑制作用。平行地，我们在2.8 A下确定LeuT-E290S的结构，LeuT-E290S是一种突变体，与LeuT-WT一样，可结合2个底物分子。这种结构与野生型相似，并且清楚地在S2位点揭示了OG分子。我们还观察到LeuT-WT晶体中S2位的电子密度，这也由该位的OG分子解释。基于LeuT可用晶体结构的计算分析表明，LeuT细胞外区域的结构排列的性质使底物的作用与结合在S2位点的抑制剂的作用区分开。我们得出的结论是，目前所有的LeuT晶体结构都在OG中得到了解决，它们代表了转运蛋白的功能受阻形式，而结合在S2位点上的底物将促进Na +偶联共存所必需的不同状态。

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    Matthias Quick; Anne-Marie Lund Winther; Lei Shi; Poul Nissen; Harel Weinstein; Jonathan A. Javitch;

  • 作者单位

    Center for Molecular Recognition and Surgeons, 630 West 168th Street, New York, NY 10032 Departments of Psychiatry and Surgeons, 630 West 168th Street, New York, NY 10032 Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY 10032;

    Department of Molecular Biology, University of Aarhus, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark;

    Department of Physiology and Biophysics and the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021;

    Departments of Psychiatry and Surgeons, 630 West 168th Street, New York, NY 10032;

    Department of Physiology and Biophysics and the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021;

    Center for Molecular Recognition and Surgeons, 630 West 168th Street, New York, NY 10032 Departments of Psychiatry and Surgeons, 630 West 168th Street, New York, NY 10032 Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY 10032 Pharmacology, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    crystal; molecular dynamics simulation; neurotransmittersodium symport; second substrate (s2)-binding site; scintillation proximity binding assay;

    机译：晶体;分子动力学模拟;神经递质钠共生;第二底物（s2）结合位点;闪烁邻近结合测定;

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