A structural basis for drug-induced long QT syndrome. Mitcheson, J., Chen, J., Lin, M., Culberson, C., & Sanguinetti, M. Proc Natl Acad Sci U S A, 97(22):12329–12333, October, 2000. bibtex @Article{RSM:Mit2000,
author = "J.S. Mitcheson and J. Chen and M. Lin and C. Culberson
and M.C. Sanguinetti",
title = "A structural basis for drug-induced long {QT}
syndrome.",
journal = "Proc Natl Acad Sci U S A",
year = "2000",
month = oct,
volume = "97",
number = "22",
pages = "12329--12333",
robnote = "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. Acquired LQT is far more common and
is most often caused by block of cardiac HERG K(+)
channels by commonly used medications. 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
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 Ile 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 Kv
channels and should facilitate the rational design of
drugs devoid of HERG channel binding activity.",
bibdate = "Tue Oct 30 15:16:38 2001",
}
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