文章基本信息

标题：Probing the molecular basis of hERG drug block with unnatural amino acids
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作者：Logan C. Macdonald ; Robin Y. Kim ; Harley T. Kurata 等
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2018
卷号：8
期号：1
页码：289
DOI：10.1038/s41598-017-18448-x
语种：English
出版社：Springer Nature
摘要：11.1 (hERG), is uniquely susceptible to high-affinity block by a wide range of drug classes. Pore residues Tyr652 and Phe656 are critical to potent drug interaction with hERG. It is considered that the molecular basis of this broad-spectrum drug block phenomenon occurs through interactions specific to the aromatic nature of the side chains at Tyr652 and Phe656. In this study, we used nonsense suppression to incorporate singly and doubly fluorinated phenylalanine residues at Tyr652 and Phe656 to assess cation-π interactions in hERG terfenadine, quinidine, and dofetilide block. Incorporation of these unnatural amino acids was achieved with minimal alteration to channel activation or inactivation gating. Our assessment of terfenadine, quinidine, and dofetilide block did not reveal evidence of a cation-π interaction at either aromatic residue, but, interestingly, shows that certain fluoro-Phe substitutions at position 652 result in weaker drug potency.