SUNY at Albany
June 19-23, 2001
Solution Conformation of the Tachykinin Peptide Eledoisin
Eledosin, a undecapeptide of mollusc origin, with the sequence pGlu-Pro-Ser-Lys-Asp-Ala-Phe-Ile-Gly-Leu-Met-NH2 ,is a member of the tachykinin family of neuropeptides. It was first isolated from the salivary glands of mollusc (Eledone muschata ). All tachykinin peptides share the same consensus C-terminal sequence, viz. Phe-Xxx-Gly-Leu-Met-NH2. This common region, often referred as the message domain, is believed to be responsible for activating the receptor. The divergent N-terminal region or the address domain varies in amino acid sequence and length and is believed to play a role in determining the receptor subtype specificity. Tachykinins exhibit vast and complex pharmacological and physiological actions, such as, powerful vasodilation, hypertensive action and stimulation of extra-vascular smooth muscle. There is considerable interest in these peptides as potential targets for drug design.
To better understand the structural basis of biological activity of eledoisin, the aqueous and lipid-induced structure of Eledosin has been studied by two-dimensional proton nuclear magnetic resonance (2D 1H-NMR) spectroscopy and distance geometry calculations. Unambiguous NMR assignments of protons have been made with the aid of correlation spectroscopy (DQF-COSY and TOCSY) experiments and nuclear Overhauser effect spectroscopy (NOESY and ROESY) experiments. The distance constraints obtained from the NMR data have been utilized in a distance geometry algorithm to generate a family of structures, which have been refined using restrained energy minimization and dynamics.CD spectropolarimetry has been used to study the effect of solvent on peptide folding. These data show that, while in water and DMSO Eledosin prefers to be in an extended chain conformation, in the presence of perdeuterated dodecylphosphocholine (DPC) micelles, a membrane model system, helical conformation is induced in the C-terminal region of the peptide. N-terminus though less defined also displays some degree of order and a possible turn structure. The results are expected to provide a possible structure for NK2- receptor selective ligands.
R. Christy Rani Grace1, Indu Chandrashekar2 and Sudha M. Cowsik2*
(1)Department of Physics, Indian Institute of Science, Bangalore ? 560 012, INDIA (2)School of Life Sciences, Jawaharlal Nehru University, New Delhi ? 110 067, INDIA *Phone 91 11 6177359:91 11 6170016; Fax: 91 11 6165886: 91 11 6187338; E.mail :scowsik@h