Mapping the binding site of melanocortin 4 receptor agonists: a hydrophobic pocket formed by I3.28(125), I3.32(129), and I7.42(291) is critical for receptor activation.

The melanocortin 4 receptor is involved in the control of the feeding behavior and energy homeostasis. It is regulated by internal agonist (alpha-MSH) and antagonists (Agouti). Peptide agonists bind in a beta-turn conformation that organizes the characteristic message sequence (His-L/DPhe-Arg-Trp) in an optimal arrangement for binding and activation of the receptor. Our goal is to determine the most likely binding modes of peptide and small molecule agonists to use this information to guide our structure-based drug design efforts. Previous studies have identified some residues that are likely to be involved in peptide agonist binding, giving an initial estimate of the main contacts between peptides and receptor. However, a more detailed description of the orientation of the peptide in a beta-turn conformation in the binding site, as well as of the small molecule agonists, and it is commonalities with the peptide agonist binding modes is necessary to serve as the basis for structure-based drug design. In the current study we combine site-directed mutagenesis with molecular modeling studies to determine the most likely binding mode of peptide and small molecule agonists, and we found that Y6.58(268), Y7.38(287), I3.28(125), I3.32(129), and I7.42(291) also line the binding site and are likely to have direct contacts with the MC4R agonists. Of particular interest are residues I3.28(125), I3.32(129), and I7.42(291), which form a hydrophobic pocket where I7.42(291), on top of the NPXXY motif, is likely to act as a new rotamer switch implicated in the activation of the receptor.

Recovering from an interruption: investigating speed-accuracy trade-offs in task resumption behavior.

Interruptions are disruptive because they take time to recover from, in the form of a resumption lag, and lead to an increase in the likelihood of errors being made. Despite an abundance of work investigating the effect of interruptions on routine task performance, little is known about whether there is a link between how quickly a task is resumed following an interruption (i.e., the duration of the postinterruption resumption lag) and the likelihood that an error is made. Two experiments are reported in which participants were interrupted by a cognitively demanding secondary mental arithmetic task while working on a routine sequential data-entry task. In Experiment 1 the time-cost of making an error on the primary task was varied between conditions. When errors were associated with a high time-cost penalty, participants made fewer errors and resumed the primary task more slowly than when errors were associated with a low time-cost penalty. In Experiment 2 participants were prohibited from resuming the primary task quickly by a 10-s system lockout period following the completion of the interrupting task. This lockout period led to a significant reduction in resumption errors because the lockout prohibited fast, inaccurate task resumptions. Taken together, our results suggest that longer resumption lags following an interruption are beneficial in terms of reducing the likelihood of errors being made. We discuss the practical implications of how systems might be designed to encourage more reflective task resumption behavior in situations where interruptions are commonplace. (PsycINFO Database Record (c) 2013 APA, all rights reserved).