Pharmacological inhibition of cardiac hERG K+ channels is associated with increased risk of lethal arrhythmias. Many drugs reduce hERG current by directly binding to the channel, thereby blocking ion conduction. Mutation of two aromatic residues (F656 and Y652) substantially decreases the potency of numerous structurally diverse compounds. Nevertheless, some drugs are only weakly affected by mutation Y652A. In this study we utilize molecular dynamics simulations and docking studies to analyze the different effects of mutation Y652A on a selected number of hERG blockers. MD simulations reveal conformational changes in the binding site induced by mutation Y652A. Loss of π-π-stacking between the two aromatic residues induces a conformational change of the F656 side chain from a cavity facing to cavity lining orientation. Docking studies and MD simulations qualitatively reproduce the diverse experimentally observed modulatory effects of mutation Y652A and provide a new structural interpretation for the sensitivity differences.

Studies on the odorant receptor cluster located on human chromosome 17, which contains 18 odorant receptor genes, are presented. After an extended search for orthologues of those odorant receptor genes in chimpanzee, rat and mouse genomes, comparisons subject to genomic location, similarities and function were made. Different ways of evolutionary propagation can be observed. This leads to conversion into pseudogenes, but also duplication of some genes occurs.

Single nucleotide polymorphisms (SNPs) in odorant receptor genes may influence the protein sequence and consequently also the function of the receptors. An analysis of the HapMap data for human OR3A1 was performed and provided evidence that genetic differences subject to ancestry and gender can be recognized. A genomic comparison of individuals shows the diversity of odorant receptor genes and therefore potentially the variety of the sense of smell. At this time, two complete human genomes are available in public domain, which we used for this purpose.

rectification. A genetically encoded Eag domain fragment (amino acids 1-135) was shown to restore slow deactivation to N-truncated channels. Our present study sought to further investigate Eag domain contributions to hERG gating kinetics. We coexpressed the genetically encoded Eag domain fragment (N1-135) with hERG channels bearing a deletion of the N-terminus in Xenopus oocytes and measured current with two-electrode voltage-clamp recordings. Here we report that coexpression with the N1-135 peptide led to a reduction in relative outward current and slowed recovery from inactivation resulting in channels with properties similar to those measured in wild-type hERG. Through regulation of deactivation and inactivation gating, the Eag domain determines the physiologically critical resurgent component of hERG current via a non-covalent interaction with the channel.