Structural changes under low evolutionary constraint may decrease the affinity of dibenzoylhydrazine insecticides for the ecdysone receptor in non‐lepidopteran insects

Abstract

Understanding how variations in genetic sequences are conveyed into structural and biochemical properties is of increasing interest in the field of molecular evolution. In order to gain insight into this process, we studied the ecdysone receptor (EcR), a transcription factor that controls moulting and metamorphosis in arthropods. Using an in silico homology model, we identified a region in the lepidopteran EcR that has no direct interaction with the natural hormone but is under strong evolutionary constraint. This region causes a small indentation in the three-dimensional structure of the protein which facilitates the binding of tebufenozide. Non-Mecopterida are considered much older, evolutionarily, than Lepidoptera and they do not have this extended cavity. This location shows differences in evolutionary constraint between Lepidoptera and other insects, where a much lower constraint is observed compared with the Lepidoptera. It is possible that the higher flexibility seen in the EcR of Lepidoptera is an entirely new trait and the higher constraint could then be an indication that this region does have another important function. Finally, we suggest that Try123, which is evolutionarily constrained and is up to now exclusively present in Lepidoptera EcRs, could play a critical role in discriminating between steroidal and non-steroidal ligands.

A new dibenzoylhydrazine with insecticidal activity against Anopheles mosquito larvae

“…This agrees with the crystal structure that was previously demonstrated for the DHB‐based BYI06830 compound in complex with the HvEcR‐LBD, in which the aliphatic chain of PonA and the t ‐butyl group of BYI06830 are anchored in a highly hydrophobic region. However, in contrast to the models that were reported before for the EcR‐LBDs of neuropteran and hymenopteran insects, the DBHs are accommodated in a different orientation in the Anopheles receptor that allows binding in the LBP (Fig. , middle and left‐hand panels).…”

“…Here, the orientation of non‐steroidal DBH molecules in the binding pocket enables them to undergo both hydrophobic and hydrophilic interactions which support their binding geometry. Overall, the docking studies support the binding of DBHs (KU‐106 and halofenozide, but also methoxyfenozide and tebufenozide; data not shown) in the LBP of AgaEcR‐LBD, although the orientation differs from that observed in the crystal structure of lepidopteran HvEcR‐LBD …”

“…DBH compounds have attracted considerable interest because of their high safety profile against vertebrates but also because of their non‐toxicity against insect predators such as neuropterans and parasitic wasps, which are used in biological control and IPM programmes. Interestingly, modelling studies indicated steric hindrance of binding of DBHs in the LBP of EcR/USP(RXR) of members of these groups, which is in contrast to the observation of efficient docking in EcR/USP(RXR) of Anopheles (Fig. ).…”

Synthesis, Crystal Structure, DFT Study of m-Methoxy-N′-(3-Methoxybenzoyl)-N-Phenylbenzohydrazide

“…The insecticidal activity of diacylhydrazine derivatives has been extensively studied by many researchers; in addition, diacylhydrazines are very useful synthons for the synthesis of a variety of bioactive molecules [1][2][3][4][5].…”

Selectivity of diacylhydrazine insecticides to the predatory bug Orius laevigatus: in vivo and modelling/docking experiments

“…The structures of the nuclear receptors have provided important information about ligand recognition and the activation mechanism of nuclear receptors. In fact, homology models based on a comparison of the EcR‐LBD with known crystal structures have been employed to determine the three‐dimensional (3D) structure of the EcR‐LBD,17 and docking studies have been carried out to simulate how a candidate ligand binds to a receptor 12, 18–20…”