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Proc Natl Acad Sci U S A
2000 Oct 24;9722:12329-33. doi: 10.1073/pnas.210244497.
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A structural basis for drug-induced long QT syndrome.
Mitcheson JS, Chen J, Lin M, Culberson C, Sanguinetti MC.
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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 and 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 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.
Abbott,
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1999, Pubmed,
Xenbase
Abbott,
MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia.
1999,
Pubmed
,
Xenbase Crumb,
QT interval prolongation by non-cardiovascular drugs: issues and solutions for novel drug development.
1999,
Pubmed Curran,
A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.
1995,
Pubmed del Camino,
Blocker protection in the pore of a voltage-gated K+ channel and its structural implications.
2000,
Pubmed Doyle,
The structure of the potassium channel: molecular basis of K+ conduction and selectivity.
1998,
Pubmed Ficker,
Molecular determinants of dofetilide block of HERG K+ channels.
1998,
Pubmed
,
Xenbase Goldin,
Expression of ion channels by injection of mRNA into Xenopus oocytes.
1991,
Pubmed
,
Xenbase Goldin,
Preparation of RNA for injection into Xenopus oocytes.
1992,
Pubmed
,
Xenbase Hockerman,
Molecular determinants of high affinity phenylalkylamine block of L-type calcium channels in transmembrane segment IIIS6 and the pore region of the alpha1 subunit.
1997,
Pubmed Hockerman,
Molecular determinants of high affinity phenylalkylamine block of L-type calcium channels.
1995,
Pubmed Kass,
Channel structure and drug-induced cardiac arrhythmias.
2000,
Pubmed Keating,
Molecular genetic insights into cardiovascular disease.
1996,
Pubmed Lees-Miller,
Molecular determinant of high-affinity dofetilide binding to HERG1 expressed in Xenopus oocytes: involvement of S6 sites.
2000,
Pubmed
,
Xenbase Lynch,
Cardiac electrophysiologic and antiarrhythmic actions of two long-acting spirobenzopyran piperidine class III agents, L-702,958 and L-706,000 [MK-499].
1994,
Pubmed Miller,
FLOG: a system to select 'quasi-flexible' ligands complementary to a receptor of known three-dimensional structure.
1994,
Pubmed Mitcheson,
Trapping of a methanesulfonanilide by closure of the HERG potassium channel activation gate.
2000,
Pubmed
,
Xenbase Mohammad,
Blockage of the HERG human cardiac K+ channel by the gastrointestinal prokinetic agent cisapride.
1997,
Pubmed Peterson,
Analysis of the dihydropyridine receptor site of L-type calcium channels by alanine-scanning mutagenesis.
1997,
Pubmed Ragsdale,
Common molecular determinants of local anesthetic, antiarrhythmic, and anticonvulsant block of voltage-gated Na+ channels.
1996,
Pubmed Roden,
Mechanisms and management of proarrhythmia.
1998,
Pubmed Roden,
Multiple mechanisms in the long-QT syndrome. Current knowledge, gaps, and future directions. The SADS Foundation Task Force on LQTS.
1996,
Pubmed Roy,
HERG, a primary human ventricular target of the nonsedating antihistamine terfenadine.
1996,
Pubmed
,
Xenbase Sanguinetti,
Mutations of the S4-S5 linker alter activation properties of HERG potassium channels expressed in Xenopus oocytes.
1999,
Pubmed
,
Xenbase Sanguinetti,
A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel.
1995,
Pubmed
,
Xenbase Smith,
The inward rectification mechanism of the HERG cardiac potassium channel.
1996,
Pubmed Spector,
Class III antiarrhythmic drugs block HERG, a human cardiac delayed rectifier K+ channel. Open-channel block by methanesulfonanilides.
1996,
Pubmed
,
Xenbase Stühmer,
Electrophysiological recording from Xenopus oocytes.
1992,
Pubmed
,
Xenbase Trudeau,
HERG, a human inward rectifier in the voltage-gated potassium channel family.
1995,
Pubmed Wang,
Modulation of HERG affinity for E-4031 by [K+]o and C-type inactivation.
1997,
Pubmed
,
Xenbase Wang,
Time, voltage and ionic concentration dependence of rectification of h-erg expressed in Xenopus oocytes.
1996,
Pubmed
,
Xenbase Warmke,
A family of potassium channel genes related to eag in Drosophila and mammals.
1994,
Pubmed Zou,
Single HERG delayed rectifier K+ channels expressed in Xenopus oocytes.
1997,
Pubmed
,
Xenbase
