title: Physicochemical features of the HERG channel drug binding site.
abstract: Blockade of hERG K(+) channels in the heart is an unintentional side effect of many drugs and can induce cardiac arrhythmia and sudden death. It has become common practice in the past few years to screen compounds for hERG channel activity early during the drug discovery process. Understanding the molecular basis of drug binding to hERG is crucial for the rational design of medications devoid of this activity. We previously identified 2 aromatic residues, Tyr-652 and Phe-656, located in the S6 domain of hERG, as critical sites of interaction with structurally diverse drugs. Here, Tyr-652 and Phe-656 were systematically mutated to different residues to determine how the physicochemical properties of the amino acid side group affected channel block by cisapride, terfenadine, and MK-499. The potency for block by all three drugs was well correlated with measures of hydrophobicity, especially the two-dimensional approximation of the van der Waals hydrophobic surface area of the side chain of residue 656. For residue 652, an aromatic side group was essential for high affinity block, suggesting the importance of a cation-pi interaction between Tyr-652 and the basic tertiary nitrogen of these drugs. hERG also lacks a Pro-Val-Pro motif common to the S6 domain of most other voltage-gated K(+) channels. Introduction of Pro-Val-Pro into hERG reduced sensitivity to drugs but also altered channel gating. Together, these findings assign specific residues to receptor fields predicted by pharmacophore models of hERG channel blockers and provide a refined molecular understanding of the drug binding site.
authors.affiliation: Department of Physiology and Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah 84112, USA.
authors.forename: David
authors.initials: D
authors.lastname: Fernandez
authors.forename: Azad
authors.initials: A
authors.lastname: Ghanta
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Kauffman
authors.forename: Michael C
authors.initials: MC
authors.lastname: Sanguinetti
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D001665:Binding Sites; D055592:Biophysical Phenomena; D001703:Biophysics; D027682:Cation Transport Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020117:Cisapride / Q000494:pharmacology; D051638:Ether-A-Go-Go Potassium Channels; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D010649:Phenylalanine / Q000737:chemistry; D010880:Piperidines / Q000494:pharmacology; D017354:Point Mutation; D015221:Potassium Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018075:RNA, Complementary / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013696:Temperature; D016593:Terfenadine / Q000737:chemistry / Q000494:pharmacology; D014443:Tyrosine / Q000737:chemistry; D014981:Xenopus
chemical_list: D001578:Benzopyrans; D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; D006634:Histamine H1 Antagonists; C092509:KCNH6 protein, human; D010880:Piperidines; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D018075:RNA, Complementary; D017366:Serotonin Receptor Agonists; C087257:L 706000; D014443:Tyrosine; D010649:Phenylalanine; D016593:Terfenadine; D020117:Cisapride