The yeast gene, GRC5 (growth control), is a member of the highly conserved QM gene family, the human member of which has been associated with the suppression of Wilms' tumor. GRC5 encodes ribosomal protein L10, which is thought to play a regulatory role in the translational control of gene expression. A revertant screen identified four spontaneous revertants of the mutant grc5-1ts allele. Genetic and phenotypic analysis showed that these represent one gene, NMD3, and that the interaction of NMD3 and GRC5 is gene-specific. NMD3 was previously identified as a component of the nonsense-mediated mRNA decay pathway. The point mutations within NMD3 reported here may define a domain important for the functional interaction of Grc5p and Nmd3p.

We present a novel method to improve a simple pair potential of mean force, derived from experimentally determined protein structures, in such a way that it recognizes native protein folds with high reliability. This improvement is based on the use of mutation data matrices to overcome difficulties arising from the poor statistics of small sample sizes. A set of 167 protein chains taken from the Brookhaven Protein Structure Data Base, selected from high-resolution structures and avoiding homologous proteins, is used for generation of the potential set. The potential describes interresidue pair energies depending on distance and sequential separation, and is calculated using the Boltzmann equation. Its performance is evaluated by jackknife tests that try to identify the native fold for a given sequence among a large number of possible threadings on all structures in the set without allowing for gaps. Up to 94% of the protein chains are correctly assigned to their native folds, so that all proper single-chain domains are recognized.

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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.

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