Abstract
Allatostatins (AST) are neuropeptides with variable function ranging from regulation of developmental processes to the feeding behavior in insects. They exert their effects by binding to cognate GPCRs, called Allatostatin receptors (AlstR), which emerge as promising targets for pesticide design. However, AlstRs are rarely studied. This study is the first reported structural study on AlstR-AST interaction. In this work, the first C type AlstR from the stick insect Carausius morosus (CamAlstR-C) was identified and its interaction with type C AST peptide was shown to be physically consistent with the experimental results. The proposed structure of CamAlstR-C revealed a conserved motif within the third extracellular loop, which, together with the N-terminus is essential for ligand binding. In this work, computational studies were combined with molecular and nano-scale approaches in order to introduce an unknown GPCR-ligand system. Consequently, the data obtained provided a reliable target region for future agonist/inverse agonist studies on AlstRs.
Highlights
Allatostatin receptors (AlstR) are insect GPCRs, which function in inhibition of Juvenile Hormone (JH) synthesis in corpora allata during development
Maximum likelihood analysis showed that this novel GPCR was closely related to type C AlstRs of other insect species (Fig. 1), which are homologous to mammalian somatostatin receptors (SSTR)
A genus-specific conservation pattern was detected within 3 genera, and CamAlstR-C showed a significant diversity from this profile
Summary
Allatostatin receptors (AlstR) are insect GPCRs, which function in inhibition of Juvenile Hormone (JH) synthesis in corpora allata during development. They play a role during oogenesis, vitellogenesis and muscle contraction in midgut, either directly or indirectly via inhibiting JH1–3. Single molecule force spectroscopy via AFM has been used successfully on living cells to measure the strength of ligand binding of transporter proteins[12] and integrins[13] while the same studies on GPCRs are limited[14]. The combination of bioinformatics, site directed mutagenesis and single molecule force spectroscopy (SMFS) allowed us to reveal its binding pocket. The methodology used in this study may provide an applicable method for further studies on the binding pocket of GPCRs, that would allow for the design of agonist/inverse agonists
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