Background: TASK-3 is gated cooperatively by extracellular pH. Results: Mutual electrostatic interaction between K ϩ ions and two pH-sensing histidines occurs in a recently discovered

A1899 is a potent and selective inhibitor of the two-pore domain potassium (K) channel TASK-1. It was previously reported that A1899 acts as an open-channel blocker and binds to residues of the P1 and P2 regions, the M2 and M4 segments, and the halothane response element. The recently described crystal structures of K channels together with the newly identified side fenestrations indicate that residues relevant for TASK-1 inhibition are not purely facing the central cavity as initially proposed. Accordingly, the TASK-1 binding site and the mechanism of inhibition might need a re-evaluation. We have used TASK-1 homology models based on recently crystallized K channels and molecular dynamics simulation to demonstrate that the highly potent TASK-1 blocker A1899 requires binding to residues located in the side fenestrations. Unexpectedly, most of the previously described residues that interfere with TASK-1 blockade by A1899 project their side chains toward the fenestration lumina, underlining the relevance of these structures for drug binding in K channels. Despite its hydrophobicity, A1899 does not seem to use the fenestrations to gain access to the central cavity from the lipid bilayer. In contrast, binding of A1899 to residues of the side fenestrations might provide a physical "anchor", reflecting an energetically favorable binding mode that after pore occlusion stabilizes the closed state of the channels.

TASK-3 is a two-pore domain potassium (K2P) channel highly expressed in the hippocampus, cerebellum, and cortex. TASK-3 has been identified as an oncogenic potassium channel and it is overexpressed in different cancer types. For this reason, the development of new TASK-3 blockers could influence the pharmacological treatment of cancer and several neurological conditions. In the present work, we searched for novel TASK-3 blockers by using a virtual screening protocol that includes pharmacophore modeling, molecular docking, and free energy calculations. With this protocol, 19 potential TASK-3 blockers were identified. These molecules were tested in TASK-3 using patch clamp, and one blocker (DR16) was identified with an IC50 = 56.8 ± 3.9 μM. Using DR16 as a scaffold, we designed DR16.1, a novel TASK-3 inhibitor, with an IC50 = 14.2 ± 3.4 μM. Our finding takes on greater relevance considering that not many inhibitory TASK-3 modulators have been reported in the scientific literature until today. These two novel TASK-3 channel inhibitors (DR16 and DR16.1) are the first compounds found using a pharmacophore-based virtual screening and rational drug design protocol.

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Common bean is one of the most important legumes produced and consumed worldwide because it is a highly valuable food for the human diet. However, its production is mainly carried out by small farmers, who obtain average grain yields below the potential yield of the species. In this sense, numerous mapping studies have been conducted to identify quantitative trait loci (QTL) associated with yield components in common bean. Meta-QTL (MQTL) analysis is a useful approach to combine data sets and for creating consensus positions for the QTL detected in independent studies. Consequently, the objective of this study was to perform a MQTL analysis to identify the most reliable and stable genomic regions associated with yield-related traits of common bean. A total of 667 QTL associated with yield-related traits reported in 21 different studies were collected. A total of 42 MQTL associated with yield-related traits were identified, in which the average confidence interval (CI) of the MQTL was 3.41 times lower than the CIs of the original QTL. Most of the MQTL (28) identified in this study contain QTL associated with yield and phenological traits; therefore, these MQTL can be useful in common bean breeding programs. Finally, a total of 18 candidate genes were identified and associated with grain yield within these MQTL, with functions related to ubiquitin ligase complex, response to auxin, and translation elongation factor activity.