Jackson Graham E, Pavadai Elumalai, Gäde Gerd, Andersen Niels H
Department of Chemistry, University of Cape Town, Cape Town, Western Cape, South Africa.
Department of Physiology and Biophysics, Boston University, Boston, MA, USA.
PeerJ. 2019 Aug 30;7:e7514. doi: 10.7717/peerj.7514. eCollection 2019.
Neuropeptides exert their activity through binding to G protein-coupled receptors (GPCRs). GPCRs are well-known drug targets in the pharmaceutical industry and are currently discussed as targets to control pest insects. Here, we investigate the neuropeptide adipokinetic hormone (AKH) system of the desert locust . The desert locust is known for its high reproduction, and for forming devastating swarms consisting of billions of individual insects. It is also known that produces three different AKHs as ligands but has only one AKH receptor (AKHR). The AKH system is known to be essential for metabolic regulation, which is necessary for reproduction and flight activity.
Nuclear magnetic resonance techniques (NMR) in a dodecylphosphocholin (DPC) micelle solution were used to determine the structure of the three AKHs. The primary sequence of the AKHR was used to construct a 3D molecular model. Next, the three AKHs were individually docked to the receptor, and dynamic simulation of the whole ligand-receptor complex in a model membrane was performed.
Although the three endogenous AKHs of have quite different amino acids sequences and chain length (two octa- and one decapeptide), NMR experiments assigned a turn structure in DPC micelle solution for all. The GPCR-ModSim program identified human kappa opioid receptor to be the best template after which the AKHR was modeled. All three AKHs were found to have the same binding site on this receptor, interact with similar residues of the receptor and have comparable binding constants. Molecular switches were also identified; the movement of the receptor could be visually shown when ligands (AKHs) were docked and the receptor was activated.
The study proposes a model of binding of the three endogenous ligands to the one existing AKHR in the desert locust and paves the way to use such a model for the design of peptide analogs and finally, peptide mimetics, in the search for novel species-specific insecticides based on receptor-ligand interaction.
神经肽通过与G蛋白偶联受体（GPCRs）结合发挥其活性。GPCRs是制药行业中众所周知的药物靶点，目前也被作为控制害虫的靶点进行讨论。在此，我们研究沙漠蝗虫的神经肽促脂动激素（AKH）系统。沙漠蝗虫以其高繁殖率以及形成由数十亿只个体昆虫组成的毁灭性蝗群而闻名。还已知其产生三种不同的AKHs作为配体，但只有一种AKH受体（AKHR）。已知AKH系统对代谢调节至关重要，而代谢调节对于繁殖和飞行活动是必需的。
使用十二烷基磷酸胆碱（DPC）胶束溶液中的核磁共振技术（NMR）来确定三种AKHs的结构。利用AKHR的一级序列构建三维分子模型。接下来，将三种AKHs分别对接至该受体，并在模型膜中对整个配体 - 受体复合物进行动力学模拟。
尽管沙漠蝗虫的三种内源性AKHs具有相当不同的氨基酸序列和链长（两条八肽和一条十肽），但NMR实验确定它们在DPC胶束溶液中均具有一个转角结构。GPCR - ModSim程序确定人类κ阿片受体是构建沙漠蝗虫AKHR模型的最佳模板。发现所有三种AKHs在该受体上具有相同的结合位点，与受体的相似残基相互作用且具有相当的结合常数。还鉴定出了分子开关；当配体（AKHs）对接且受体被激活时，可以直观地显示受体的运动。
该研究提出了沙漠蝗虫中三种内源性配体与一种现有AKHR的结合模型，为基于受体 - 配体相互作用设计肽类似物以及最终的肽模拟物以寻找新型物种特异性杀虫剂铺平了道路。
