Lipid-induced Conformation of Substance P

Abstract

Both the aqueous and the lipid-induced structure of a representative and widely studied tachykinin, substance P, has been investigated 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 (COSY and TOCSY) experiments and Overhauser enhancement spectroscopy (ROESY and NOESY; experiments. The NMR data obtained were utilized in a distance geometry algorithm to generate a family of structures which were further refined using restrained energy minimization. These data show that, while in water substance P appears to favour an extended chain conformation, in the presence of perdeuterated dodecylphosphocholine (DPC) micelles as membrane model system an amphiphilic helical conformation is induced in the mid-region (Q5-Q8) of substance P. The conformation adopted by substance P in the presence of DPC micelles yields a structural motif typical of neurokinin-1 selective ligands, as proposed by Convert and coworkers (O. Convert et al., Neuropeptides 19, 259-270 (1991)).

Pharmacophore Pattern Identification of Tachykinin Receptor Selective Peptide Agonists: Implications in Receptor Selectivity

“…Bioactive conformation of tachykinin neuropeptides has been extensively investigated using high-resolution nuclear magnetic resonance (NMR), circular dichroism (CD) and Infrared (IR) spectroscopy. Solution structure for SP, NKA, NKB, Physalaemin, Eledoisin and various naturally derived or synthetic analogues has been reported in various membrane mimetic solvents [12][13][14][15][16][17][18][19][20][21][22][23][24][25] . We present here a brief summary of threedimensional structure of tachykinin neuropeptides (NK1, NK2 and NK3 receptor agonists) bound to dodecylphosphocholine (DPC) micelles, one of the well-characterized model membrane systems, using two-dimensional NMR spectroscopy.…”

An NMR Study on the Conformation of Substance P in Acidic Bicelles

“…For SP in SDS and DPC micelles, no such NOE connectivity was observed. [8][9][10] Thus, it appears that the conformation of SP depends not only on the solution condition, but also on the type of model membranes, of which the bicelle with flat bilayer surface might provide a better environment for the extended helix formation than the micelle with highly curved surface. The well-aligned hydrophobic acyl chain in the flat surface can interact more effectively with the terminal region of the straight helical structure of SP.…”

“…[8][9][10] Many conformational studies indicate that SP shows no preference in conformation when dispersed in aqueous solutions, 7-11 while it favors relatively well-defined conformations in membrane mimics and organic solvents. 6,[8][9][10][11]13 In the present study, we have investigated the conformational features of SP in isotropic (q = 0.5) acidic bicelle with a flat bilayer surface using two-dimensional NMR techniques. Structural analysis of NMR data suggests that SP forms a 3 10 -helix as in micelles but the helical conformation extends from Pro4 to Met11 contrary to the micellar one having a helical conformation only in the mid-region.…”

“…12,14 The results indicate that SP has a random structure in aqueous solutions, [7][8][9][10][11] whereas it exhibits helix-like turns or partial helical structures in various membrane mimetic systems such as micelles and phospholipids bilayers. 6,[8][9][10]13 In addition, SP is known to experience at least three types of lipid environments. such as the storage vesicles, the presynaptic and the postsynaptic membranes, 9 during the physiological processes.…”

“…To investigate the effects of conformation on the activity of SP, extensive conformational studies have been conducted for the past several decades using diverse techniques such as circular dichroism, 3,4 infrared spectroscopy, 5 nuclear magnetic resonance (NMR), [6][7][8][9][10][11][12][13] and molecular dynamics. 12,14 The results indicate that SP has a random structure in aqueous solutions, [7][8][9][10][11] whereas it exhibits helix-like turns or partial helical structures in various membrane mimetic systems such as micelles and phospholipids bilayers.…”