Anopheles gambiae, Anoga-HrTH hormone, free and bound structure – A nuclear magnetic resonance experiment

    loading  Checking for direct PDF access through Ovid



★ We have determined the preferred conformation of Anoga-HrTH from Anopheles gambiae, in water and bound to a membrane. ★ We report changes in this conformation upon binding to its G-protein coupled receptor. ★ The interaction between Anoga-HrTH and its receptor were used to explain structure-activity data. ★ The Anoga-HrTH/AKHR complex was stabilized by both polar and hydrophobic interactions involving residues in helices and extracellular loops. ★ The estimated free energy of binding (ΔGb) and inhibition constant (Ki), are −47.3 kJ/mol and 5.2 nM respectively.

The spread of malaria by the female mosquito, Anopheles gambiae, is dependent, amongst other things, on its ability to fly. This in turn, is dependent on the adipokinetic hormone, Anoga-HrTH (pGlu-Leu-Thr-Phe-Thr-Pro-Ala-Trp-NH2). No crystal structure of this important neuropeptide is available and hence NMR restrained molecular dynamics was used to investigate its conformational space in aqueous solution and when bound to a membrane surface. The results showed that Anoga-HrTH has an almost cyclic conformation that is stabilized by a hydrogen bond between the C-terminus and Thr3. Upon docking of the agonist to its receptor, this H-bond is broken and the molecule adopts a more extended structure. Preliminary AKHR docking calculations give the free energy of binding to be −47.30 kJ/mol. There is a close correspondence between the structure of the docked ligand and literature structure–activity studies. Information about the 3D structure and binding mode of Anoga-HrTH to its receptor is vital for the design of suitable mimetics which can act as insecticides.

Related Topics

    loading  Loading Related Articles