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首页> 外文期刊>Journal of Molecular Biology >Molecular Determinants for Ligand Selectivity of the Cell -Free Synthesized Human Endothelin B Receptor
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Molecular Determinants for Ligand Selectivity of the Cell -Free Synthesized Human Endothelin B Receptor

机译：细胞配体选择性的分子决定因素 - 完全合成的人内皮素B受体

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摘要

Extracellular domains of G-protein-coupled receptors act as initial molecular selectivity filters for subtype specific ligands and drugs. Chimeras of the human endothelin-B receptor containing structural units from the extracellular domains of the endothelin-A receptor were analyzed after their co-translational insertion into preformed nanodiscs. A short beta-strand and a linker region in the second extracellular loop as well as parts of the extracellular N-terminal domain were identified as molecular discrimination sites for the endothelin-B receptor-selective agonists IRL1620, sarafotoxin 6c, 4Ala-ET-1 and ET-3, but not for the non-selective agonist ET-1 recognized by both endothelin receptors. A proposed second disulfide bridge in the endothelin-B receptor tethering the N-terminal domain with the third extracellular loop was not essential for ET-1 recognition and binding, but increased the receptor thermostability. We further demonstrate an experimental approach with cell-free synthesized engineered agonists to analyze the differential discrimination of peptide ligand topologies by the two endothelin receptors. The study is based on the engineering and cell-free insertion of G-protein-coupled receptors into defined membranes and may become interesting also for other targets as an alternative platform to reveal molecular details of ligand selectivity and ligand binding mechanisms. (C) 2018 Elsevier Ltd. All rights reserved.
机译：G蛋白偶联受体的细胞外结构域用作亚型特异性配体和药物的初始分子选择性过滤器。在将含有内皮素-A受体的细胞外结构域中的含有结构单元的人内皮素-B受体的嵌合体在将其副平移插入预成型的纳米纳米氏菌中分析。第二细胞外环中的短β-链和接头区域以及细胞外N-末端结构域的部分鉴定为内皮素-B受体选择性激动剂IRL1620，Sarafotoxin 6c，4ala-et-1的分子辨别位点。和ET-3，但不适用于内皮素受体识别的非选择性激动剂ET-1。内皮素-B受体中所提出的第二二硫化物桥与第三细胞外环的N-末端结构孔不属于ET-1识别和结合，而是增加受体热稳定性。我们进一步证明了一种具有无细胞合成工程激动剂的实验方法，以分析两种内皮素受体的肽配体拓扑的差分辨别。该研究基于G蛋白偶联受体的工程和无细胞插入型膜中，也可能成为其他靶标作为替代平台，以揭示配体选择性和配体结合机构的分子细节。 （c）2018年elestvier有限公司保留所有权利。

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