Probing the molecular basis of hERG drug block with unnatural amino acids.

ABSTRACT: Repolarization of the cardiac action potential is primarily mediated by two voltage-dependent potassium currents: I _Kr and I _Ks . The voltage-gated potassium channel that gives rise to I _Kr, K_v11.1 (hERG), is uniquely susceptible to high-affinity block by a wide range of drug classes. Pore residues Tyr652 and Phe656 are critical to potent drug interaction with hERG. It is considered that the molecular basis of this broad-spectrum drug block phenomenon occurs through interactions specific to the aromatic nature of the side chains at Tyr652 and Phe656. In this study, we used nonsense suppression to incorporate singly and doubly fluorinated phenylalanine residues at Tyr652 and Phe656 to assess cation-π interactions in hERG terfenadine, quinidine, an

SUBMITTER: Macdonald LC 

PROVIDER: S-EPMC5762913 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature