Identifies a key amino acid residue (position 647) in the HERG channel that indirectly maintains high affinity for drug binding, relevant for understanding drug-induced arrhythmias.
Residue 647 variants merit caution in HERG drug screening models; leaves open their impact on clinical arrhythmia risk.
We did the experiments to search for amino acids that affect quinidine binding to the HERG channel, and have identified an amino acid whose change by mutation affects the binding of various drugs. The residue is located at position 647 in the S6 and is not involved in the recently identified methanesulfonanilide binding pocket. The homology model of the HERG channel indicated that the residue faces toward the outside of the channel pore. We conclude that the residue at position 647 does not interact directly with drug molecules but plays an important role in keeping the binding site's high affinity for drugs.
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Ishii et al. (2001) studied this question.
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