Mechanism of enhanced sensitivity of mutated β‐adrenergic‐like octopamine receptor to amitraz in honeybee Apis mellifera: An insight from MD simulations

Abstract

BACKGROUND: Amitraz is one of the critical acaricides/insecticides for effective control of pest infestation of Varroa destructor mite, a devastating parasite of Apis mellifera, because of its low toxicity to honeybees. Previous assays verified that a typical G protein-coupled receptor, ⊎-adrenergic-like octopamine receptor (Oct⊎2R), is the unique target of amitraz, but the honeybee Oct⊎2R resists to amitraz. However, the underlying molecular mechanism of the enhanced sensitivity or toxicity of amitraz to mutated honeybee Oct⊎2R E208V/I335T/I350V is not fully understood. Here, molecular dynamics simulations are employed to explore the implied mechanism of the enhanced sensitivity to amitraz in mutant honeybee Oct⊎2R. RESULTS: We found that amitraz binding stabilized the structure of Oct⊎2R, particularly the intracellular loop 3 associated with the Oct⊎2R signaling. Then, it was further demonstrated that both mutations and ligand binding resulted in a more rigid and compact amitraz binding site, as well as the outward movement of the transmembrane helix 6, which was a prerequisite for G protein coupling and activation. Moreover, mutations were found to promote the binding between Oct⊎2R and amitraz. Finally, community analysis illuminated that mutations and amitraz strengthened the residue-residue communication within the transmembrane domain, which might facilitate the allosteric signal propagation and activation of Oct⊎2R. CONCLUSION: Our results unveiled structural determinants of improved sensitivity in the Oct⊎2R-amitraz complex and may contribute to further structure-based drug design for safer and less toxic selective insecticides.

Allosteric inhibition of myosin by phenamacril: a synergistic mechanism revealed by computational and experimental approaches

“…For example, GPCRs, involved in numerous cellular signal transduction, are intrinsically allosteric proteins, activated by a diverse range of extracellular ligands and transmitting external environmental signals from one part of the protein to another (from extracellular to cytoplasmic). [53][54][55][56][57][58] Besides orthosteric sites recognized by endogenous agonists, many additional sites are spatially distinct but functionally linked to the orthosteric ones either positively or negatively, further increasing the complexity of GPCR function, and both ions and small molecules can act as GPCR allosteric modulators. 59,60 In addition, the binding of the allosteric effector might induce conformational or dynamics rearrangement of the PPI interface, and thereby interrupt or disrupt the recognition and interaction between PPI partners.…”

Transcriptomic analysis of the honey bee (Apis mellifera) queen brain reveals that gene expression is affected by pesticide exposure during development

“…Amitraz is a formamidine that targets tyramine and octopamine receptors in insects [ 104 – 106 ]. We chose to focus on the DEGs in the brain tissue of queens reared in wax contaminated with amitraz partly because our previous work showed that queens reared in amitraz-laden wax laid significantly fewer eggs than queens in any other treatment group [ 26 ] We therefore aimed to find DEGs in queens from the amitraz group that were involved in egg production and identified five genes of interest: GB40823 (Vitellogenin receptor), GB49544 (Vitellogenin), GB50425 (Maternal gene required for meiosis), GB47422 (Microtubule-associated serine/threonine-protein kinase 3), and GB45876 (Ribosomal protein S6 kinase beta-1-like) ( Fig 4 ).…”