Flexibility and extracellular opening determine the interaction between ligands and insect sulfakinin receptors

Authors: YU, NA - Ghent University; ZOTTI, MOISES - Universidade Federal De Pelotas; SCHEYS, FREJA - Ghent University; BRAZ, ANTONIO - Federal University - Brazil; PENNA, PEDRO - Federal University - Brazil; Nachman, Ronald; SMAGGHE, GUY - Ghent University

Submitted to: Scientific Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/29/2015
Publication Date: 8/12/2015
Citation: Yu, N., Zotti, M.J., Scheys, F., Braz, A.S., Penna, P.H., Nachman, R.J., Smagghe, G. 2015. Flexibility and extracellular opening determine the interaction between ligands and insect sulfakinin receptors. Scientific Reports. 5:12627.

Interpretive Summary: Insect pests have developed resistance to several conventional pesticides, and new approaches are needed for pest management. Although neuropeptides (short chains of amino acids) serve as potent messengers in insects to regulate vital functions, the neuropeptides hold little promise as pest control agents because they can be degraded in the target pest. New, selective control agents may be developed by designing mimics of these neuropeptides that resist degradation and either inhibit or over-stimulate critical neuropeptide-regulated life functions. We report on the identification of structural factors on the peptide hormone as well as the active site that are critical for the interaction of sulfakinin neuropeptide hormones with two of their active sites in the red flour beetle, an important pest of stored grain. In beetles and other insects, this hormone regulates the critical functions of food intake and appetite. The research used information gleaned from the bioactivity of a series of structurally modified sulfakinin versions together with computer molecular modeling to develop the mechanism by which the hormones bind and activate their active sites. This discovery, and the new information gained from it, will aid in the design of neuropeptide-like compounds capable of disrupting the food intake and/or appetite of these and related beetles. This may eventually lead to development of practical neuropeptide-like substances that can effectively control pest insects of in an environmentally friendly fashion.

Technical Abstract: Despite their fundamental importance for growth, the mechanisms that regulate food intake are poorly understood. Our previous work demonstrated that insect sulfakinin (SK) signaling is involved in inhibiting feeding in an important model and pest insect, the red flour beetle Tribolium castaneum. Because the interaction of SK peptide and SK receptors (SKR) initiates the SK signaling, we have special interest on the structural factors that influence the SK-SKR interaction. First, the three-dimensional structures of the two T. castaneum SKRs (TcSKR1 and TcSKR2) were generated from molecular modeling and they displayed significance in terms of the outer opening of the cavity and protein flexibility. TcSKR1 contained a larger outer opening of the cavity than that in TcSKR2, which allows ligands a deep access into the cavity through cell membrane. Second, normal mode analysis revealed that TcSKR1 was more flexible than TcSKR2 during receptor-ligand interaction. Third, the sulfated SK (sSK) and sSK-related peptides were more potent than the nonsulfated SK, suggesting the importance of the sulfate moiety.