Membrane simulation of the adipokinetic hormone from the malaria mosquito: 42nd IUPAC Congress, Glasgow, Scotland, 2 – 7 August 2009

Abstract

The mosquito, Anopheles gambiae, is the major vector for the malaria parasite, Plasmodium falciparum1,2,3. Adipokinetic hormone receptor (AKHR), an insect G-protein coupled receptor (GPCR), mediates generation of energy during mosquito flight3. Despite their physiological importance, to date, no 3D structure of an insect (GPCR) is available. Here we present the 3D structure of AKHR based on beta2-adrenergic receptor. To mimic the actual environment the receptor was inserted into a model membrane and the system subjected to 100ns molecular dynamics. Docking calculations of the insect adipokinetic hormone, Del-CC (pGlu-Leu-Asn-Phe-Ser-Pro-Asn-Trp-Gly-Asn-NH2)9, show that helices 2, 3, 5, 6 and 7 residues, and the extracellular domain of the receptor participate in hormone binding. The 3D structure and binding pocket location of the adipokinetic hormone receptor from the malaria mosquito could lead to the design of non-peptide mimetics that can block the binding pocket, reduce the amount of energy available for the mosquito to fly and hence prevent transmission of malaria. References: 1. Hill, C. A. & Brown, M. R. G – protein coupled receptors in Anopheles gambiae., Science 298, 176 – 178 (2002). 2. Kaufmann, C. & Brown, M. R. Regulation of carbohydrates metabolism and flight performance by a hypertrehalosaemic hormone in the mosquito Anopheles gambiae. J. Ins. Phys. 54, 367-377 (2008). 3. Gade, G. and Auerswald, L. Flight substrates in blister beetles (Coleoptera: Meloidae) and their regulation by neuropeptides of the AKH/RPCH family. Eur. J. Entomol. 96, 331-335 (1999)