A structural basis for drug-induced long QT syndrome
A structural basis for drug-induced long QT syndrome
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DOI：
10.1073/pnas.210244497
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发表时间：
2000-10-24
影响因子：
11.1
通讯作者：
Sanguinetti, MC
中科院分区：
文献类型：
--
作者：
Mitcheson, JS;Chen, J;Sanguinetti, MC
HERG K+通道基因的突变引起遗传性长QT综合征（LQT），这是一种心脏复极障碍，其使受影响的个体易患致命性心律失常[Curran，M. E、Splawski，I，，Timothy，K. W.，Vincent，G. M.，绿色，E. D. & Keating，M. T.（1995）Cell 80，795-804]。获得性LQT更为常见，最常见的原因是常用药物阻断心脏HERG K+通道[罗登，D. M.，拉扎拉河罗森，M.，Schwartz，P. J.，Towbin，J. & Vincent，G. M.（1996）Circulation 94，1996-2012]。目前尚不清楚为什么如此多的结构不同的化合物阻断HERG通道，但这种不良副作用现在被认为是开发新的安全药物的主要障碍。在这里，我们使用丙氨酸扫描诱变，以确定高亲和力的药物阻滞HERG通道的MK-499，甲磺酰苯胺类抗肿瘤药物的结构基础。经同源性建模证实，结合位点由位于S6跨膜结构域（G648. Y 652和F656）和面向通道腔的HERG通道亚基的孔螺旋（T623酸V625）。还研究了与MK-499结构无关但引起LQT的其他化合物。抗组胺药特非那定和胃肠道促动力药西沙必利与Y 652和F656相互作用，但不与V625相互作用。与这些药物（Y 652和F656）相互作用的S6结构域的芳香族残基是eag/erg K+通道所独有的。其他电压门控K+（Kv）通道在相同位置具有Ile和瓦尔（Ile）。这些研究结果表明了一个可能的结构解释，为什么这么多常用的药物阻断HERG而不是其他Ky通道，并应促进缺乏HERG通道结合活性的药物的合理设计。
Mutations in the HERG K+ channel gene cause inherited long QT syndrome (LQT), a disorder of cardiac repolarization that predisposes affected individuals to lethal arrhythmias [Curran, M. E., Splawski, I,, Timothy, K. W., Vincent, G. M., Green, E. D. & Keating, M. T. (1995) Cell 80, 795-804]. Acquired LQT is far more common and is most often caused by block of cardiac HERG K+ channels by commonly used medications [Roden, D. M., Lazzara, R., Rosen, M., Schwartz, P. J., Towbin, J. & Vincent, G. M. (1996) Circulation 94, 1996-2012]. It is unclear why so many structurally diverse compounds block HERG channels, but this undesirable side effect now is recognized as a major hurdle in the development of new and safe drugs. Here we use alanine-scanning mutagenesis to determine the structural basis for high-affinity drug block of HERG channels by MK-499, a methanesulfonanilide antiarrhythmic drug. The binding site, corroborated with homology modeling, is comprised of amino acids located on the S6 transmembrane domain (G648. Y652, and F656) and pore helix (T623 acid V625) of the HERG channel subunit that face the cavity of the channel. Other compounds that are structurally unrelated to MK-499, but cause LQT, also were studied. The antihistamine terfenadine and a gastrointestinal prokinetic drug, cisapride, interact with Y652 and F656, but not with V625. The aromatic residues of the S6 domain that interact with these drugs (Y652 and F656) are unique to eag/erg K+ channels. Other voltage-gated K+ (Kv) channels have lie and Val (Ile) in the equivalent positions. These findings suggest a possible structural explanation for how so many commonly used medications block HERG but not other Ky channels and should facilitate the rational design of drugs devoid of HERG channel binding activity.