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Structural determinants of HERG channel block by clofilium and ibutilide.
Mol Pharmacol. 2004 Aug; 66(2):240-9.MP

Abstract

Block of human ether-a-go-go related gene (HERG) K(+) channels by a variety of medications has been linked to acquired long QT syndrome, a disorder of cardiac repolarization that predisposes to lethal arrhythmias. The drug-binding site is composed of residues that face into the central cavity of the channel. Two aromatic residues located on the S6 domain (Tyr652 and Phe656) are particularly important structural determinants of drug block. The role of pore helix residues (Thr623, Ser624, Val625) is less clear. In this study, we compared the pharmacological properties of two structurally related compounds, ibutilide and clofilium. Both compounds are charged amines with a single phenyl ring. Clofilium, a chlorobenzene derivative, is a potent blocker of HERG channels, but has a remarkably slower time course for recovery from block than ibutilide, a methanesulfonanilide. The difference in the rate of recovery from block can be explained simply by variation in drug trapping. There is little recovery from clofilium block with D540K HERG channels that permit untrapping at hyperpolarized potentials. Alanine-scanning mutagenesis of the S6 domain and a portion of the pore helix revealed that the binding site residues were the same for both compounds. However, S624A, located at the base of the pore helix, was the only HERG mutation that enabled rapid recovery from clofilium block. In summary, the pore helix residues are important components of the HERG drug binding site, and may be particularly important for drugs with polar substituents, such as a halogen (e.g., clofilium) or a methanesulfonamide (e.g., ibutilide).

Authors+Show Affiliations

University of Leicester, Department of Cell Physiology and Pharmacology, United Kingdom.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15266014

Citation

Perry, Matthew, et al. "Structural Determinants of HERG Channel Block By Clofilium and Ibutilide." Molecular Pharmacology, vol. 66, no. 2, 2004, pp. 240-9.
Perry M, de Groot MJ, Helliwell R, et al. Structural determinants of HERG channel block by clofilium and ibutilide. Mol Pharmacol. 2004;66(2):240-9.
Perry, M., de Groot, M. J., Helliwell, R., Leishman, D., Tristani-Firouzi, M., Sanguinetti, M. C., & Mitcheson, J. (2004). Structural determinants of HERG channel block by clofilium and ibutilide. Molecular Pharmacology, 66(2), 240-9.
Perry M, et al. Structural Determinants of HERG Channel Block By Clofilium and Ibutilide. Mol Pharmacol. 2004;66(2):240-9. PubMed PMID: 15266014.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structural determinants of HERG channel block by clofilium and ibutilide. AU - Perry,Matthew, AU - de Groot,Marcel J, AU - Helliwell,Ray, AU - Leishman,Derek, AU - Tristani-Firouzi,Martin, AU - Sanguinetti,Michael C, AU - Mitcheson,John, PY - 2004/7/22/pubmed PY - 2004/8/31/medline PY - 2004/7/22/entrez SP - 240 EP - 9 JF - Molecular pharmacology JO - Mol Pharmacol VL - 66 IS - 2 N2 - Block of human ether-a-go-go related gene (HERG) K(+) channels by a variety of medications has been linked to acquired long QT syndrome, a disorder of cardiac repolarization that predisposes to lethal arrhythmias. The drug-binding site is composed of residues that face into the central cavity of the channel. Two aromatic residues located on the S6 domain (Tyr652 and Phe656) are particularly important structural determinants of drug block. The role of pore helix residues (Thr623, Ser624, Val625) is less clear. In this study, we compared the pharmacological properties of two structurally related compounds, ibutilide and clofilium. Both compounds are charged amines with a single phenyl ring. Clofilium, a chlorobenzene derivative, is a potent blocker of HERG channels, but has a remarkably slower time course for recovery from block than ibutilide, a methanesulfonanilide. The difference in the rate of recovery from block can be explained simply by variation in drug trapping. There is little recovery from clofilium block with D540K HERG channels that permit untrapping at hyperpolarized potentials. Alanine-scanning mutagenesis of the S6 domain and a portion of the pore helix revealed that the binding site residues were the same for both compounds. However, S624A, located at the base of the pore helix, was the only HERG mutation that enabled rapid recovery from clofilium block. In summary, the pore helix residues are important components of the HERG drug binding site, and may be particularly important for drugs with polar substituents, such as a halogen (e.g., clofilium) or a methanesulfonamide (e.g., ibutilide). SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/15266014/Structural_determinants_of_HERG_channel_block_by_clofilium_and_ibutilide_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15266014 DB - PRIME DP - Unbound Medicine ER -