physalaemin and dodecylphosphocholine

Physalaemin (PHY), a non-mammalian tachykinin, binds selectively to neurokinin-1 (NK1) receptor with high affinity. Both the aqueous and lipid-induced conformations of PHY have been studied using two-dimensional nuclear magnetic resonance techniques. These data show that in water PHY prefers to be in an extended conformation and that in the presence of perdeuterated dodecylphosphocholine micelles, a membrane model system, a helical conformation is observed from Pro4 to the C-terminus. Comparison of the structures ofPHYand other NK ligands along with structure activity studies reported on these peptide ligands suggests that helical backbone structural motif is necessary for the binding of these NK ligands to the various NK receptors. Furthermore, consensus in the structures of these ligands suggests that these ligands must be binding along the highly hydrophobic face of the helix that contains the important hydrophobic residues, Phe7, Leu10, and Met11, that are highly conserved in most of the ligands.

Topics: Amino Acid Motifs; Amphibian Proteins; Animals; Micelles; Nuclear Magnetic Resonance, Biomolecular; Phosphorylcholine; Physalaemin; Ranidae

Uperolein, a physalaemin-like endecapeptide, has been shown to be selective for Neurokinin 1 receptor. As a first step towards understanding the structure-activity relationship, we report the membrane-induced structure of Uperolein with the aid of circular dichroism and 2D (1)H NMR spectroscopy. Sequence-specific resonance assignments of protons have been made using correlation spectroscopy (TOCSY, DQF-COSY) and NOESY spectroscopy. The interproton distance constraints and dihedral angle constraints have been utilized to generate a family of structures using torsion angle molecular dynamics within program DYANA. The conformational range of the peptide revealed by NMR and CD studies has been analysed in terms of characteristic secondary features. Analysis of NMR data indicates that the global fold of Uperolein can be explained in terms of equilibrium between 3(10)-helix and alpha-helix from residues 5 to 11. An extended highly flexible N-terminus displays some degree of order and a possible turn structure. A comparison between the structures of Uperolein and Substance P, a prototype and endogenous Neurokinin 1 receptor agonist, indicates several common features in the distribution of hydrophobic and hydrophilic residues. Both the peptides show an amphiphilic character towards the middle region. The similarities suggest that the molecules interact with the receptor in an analogous manner.

Topics: Amino Acid Sequence; Circular Dichroism; Magnetic Resonance Spectroscopy; Micelles; Models, Molecular; Phosphorylcholine; Physalaemin; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary; Sequence Homology, Amino Acid; Structure-Activity Relationship; Substance P; Tachykinins