Department of Chemistry, University of Cape Town, Private Bag, Rondebosch 7701, South Africa.
Bio21 Institute, University of Melbourne, Melbourne, VIC 3010, Australia.
Biomolecules. 2024 Mar 6;14(3):313. doi: 10.3390/biom14030313.
Neuropeptides are the main regulators of physiological, developmental, and behavioural processes in insects. Three insect neuropeptide systems, the adipokinetic hormone (AKH), corazonin (Crz), and adipokinetic hormone/corazonin-related peptide (ACP), and their cognate receptors, are related to the vertebrate gonadotropin (GnRH) system and form the GnRH superfamily of peptides. In the current study, the two signalling systems, AKH and ACP, of the yellow fever mosquito, , were comparatively investigated with respect to ligand binding to their respective receptors. To achieve this, the solution structure of the hormones was determined by nuclear magnetic resonance distance restraint methodology. Atomic-scale models of the two G protein-coupled receptors were constructed with the help of homology modelling. Thereafter, the binding sites of the receptors were identified by blind docking of the ligands to the receptors, and models were derived for each hormone system showing how the ligands are bound to their receptors. Lastly, the two models were validated by comparing the computational results with experimentally derived data available from the literature. This mostly resulted in an acceptable agreement, proving the models to be largely correct and usable. The identification of an antagonist versus a true agonist may, however, require additional testing. The computational data also explains the exclusivity of the two systems that bind only the cognate ligand. This study forms the basis for further drug discovery studies.
神经肽是昆虫生理、发育和行为过程的主要调节剂。三种昆虫神经肽系统，即脂动激素（AKH）、心激素（Crz）和脂动激素/心激素相关肽（ACP）及其同源受体，与脊椎动物促性腺激素（GnRH）系统相关，并构成了 GnRH 肽超家族。在本研究中，比较研究了黄热病蚊子的两种信号系统，AKH 和 ACP，关于它们各自的受体与配体的结合。为了实现这一目标，通过核磁共振距离约束方法确定了激素的溶液结构。借助同源建模构建了两个 G 蛋白偶联受体的原子尺度模型。此后，通过将配体盲目对接至受体来识别受体的结合位点，并为每个激素系统生成模型，展示配体如何与受体结合。最后，通过将计算结果与文献中可用的实验数据进行比较来验证两个模型。这主要导致了可以接受的一致性，证明模型基本正确且可用。然而，识别拮抗剂与真正激动剂可能需要额外的测试。计算数据还解释了两个系统的排他性，它们只结合同源配体。这项研究为进一步的药物发现研究奠定了基础。
