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.
  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}
  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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