| 1. |
- Jackson, Graham E, et al.
(författare)
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Solution conformations of an insect neuropeptide : crustacean cardioactive peptide (CCAP)
- 2009
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Ingår i: Peptides. - : Elsevier BV. - 0196-9781 .- 1873-5169. ; 30:3, s. 557-564
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Tidskriftsartikel (refereegranskat)abstract
- The solution structure of crustacean cardioactive peptide (CCAP), a cyclic amidated nonapeptide neurohormone, was studied using molecular dynamics techniques, with constraints derived from NMR studies in water and water/dodecylphosphocholine micellar medium. This peptide, found in various invertebrates, has the primary sequence Pro(1) Phe(2) Cys(3) Asn(4) Ala(5) Phe(6) Thr(7) Gly(8) Cys(9) NH(2), with an intramolecular disulfide bridge between the two cysteine residues. In aqueous solution the peptide was found to have a type(IV) beta-turn between residues 5-8. In a water/decane biphasic medium a type(IV) beta-turn between residues 3 and 6 and two classic gamma-turns between residues 4-6 and 7-9, were found. Analysis of the (1)H and (13)C NMR chemical shifts data showed that the model free S(2) order parameter of the residues varied between 0.65 and 0.9. The molecular dynamic root mean square fluctuations of structural ensembles of the backbone varied between 0.5 and 2.2 with the central residues showing the least fluctuations.
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| 2. |
- Mugumbate, Grace, et al.
(författare)
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Anopheles gambiae, Anoga-HrTH hormone, free and bound structure : A nuclear magnetic resonance experiment
- 2013
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Ingår i: Peptides. - : Elsevier BV. - 0196-9781 .- 1873-5169. ; 41, s. 94-100
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Mugumbate, Grace, et al.
(författare)
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Open conformation of adipokinetic hormone receptor from the malaria mosquito facilitates hormone binding
- 2011
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Ingår i: Peptides. - : Elsevier BV. - 0196-9781 .- 1873-5169. ; 32:3, s. 553-559
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Tidskriftsartikel (refereegranskat)abstract
- Insect flight requires rapid mobilization of energy reserves during flight, which is mediated and regulated by hormonal control via adipokinetic hormones. The structure of the G-protein receptors to which these hormones bind, are crucial in understanding many of the physiological processes in which they play a central role. To date no 3D structure of an insect G-protein coupled receptor (GPCR) is available. Here, the first models of the 3D structures of a GPCR from the malaria mosquito are presented. Homology modeling of the receptor identified from the genome of Anopheles gambiae was used to construct two models of the receptor. The 7 transmembrane helical bundles of these two models are based on the crystal structures of beta2-adrenergic receptor and rhodopsin. The flexible loop regions were modeled using high temperature simulated annealing and constrained molecular dynamic simulations. The two receptor models differ in a number of critical features, the most important of which is that the rhodopsin-based model has a 'closed' structure while the beta2-based structure is 'open'. The 'open' conformation provides easy access of the hormone to the binding pocket. Docking calculations with the insect adipokinetic hormones, AKH-1 (pGlu-Leu-Thr-Phe-Thr-Pro-Ala-Trp-NH2) from the malaria mosquito and Del-CC (pGlu-Lys-Asn-Phe-Ser-Pro-Asn-Trp-Gly-Asn-NH2) from the blister beetle showed that while the binding motif of the two is similar. AKH-1 has more than 30 times higher affinity than Del-CC, which strongly suggests that the binding is specific, and that the correct binding site was identified. Using these models it is possible to design antagonists, which block the binding site and are thus species-specific insecticides.
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