title: Structural determinants of HERG channel block by clofilium and ibutilide.
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.affiliation: University of Leicester, Department of Cell Physiology and Pharmacology, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Perry
authors.forename: Marcel J
authors.initials: MJ
authors.lastname: de Groot
authors.forename: Ray
authors.initials: R
authors.lastname: Helliwell
authors.forename: Derek
authors.initials: D
authors.lastname: Leishman
authors.forename: Martin
authors.initials: M
authors.lastname: Tristani-Firouzi
authors.forename: Michael C
authors.initials: MC
authors.lastname: Sanguinetti
authors.forename: John
authors.initials: J
authors.lastname: Mitcheson
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001224:Aspartic Acid / Q000235:genetics; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009865:Oocytes; D010627:Phenethylamines / Q000494:pharmacology; D010649:Phenylalanine / Q000235:genetics; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D012694:Serine / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology*; D014443:Tyrosine / Q000235:genetics; D014982:Xenopus laevis
chemical_list: D000889:Anti-Arrhythmia Agents; D001578:Benzopyrans; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D010627:Phenethylamines; D010880:Piperidines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines; D000644:Quaternary Ammonium Compounds; D013449:Sulfonamides; C063968:E 4031; C087257:L 706000; C067192:ibutilide; D001224:Aspartic Acid; D014443:Tyrosine; D012694:Serine; D010649:Phenylalanine; C022799:clofilium; C063533:dofetilide