Conformation-activity relationship of tachykinin neurokinin A (4-10) and of some [Xaa8] analogues.
NKA (4-10), the C-terminal heptapeptide fragment (Asp-Ser-Phe-Val-Gly-Leu-Met-NH2) of tachykinin NKA, is more active than the parent native compound in the interaction with the NK-2 receptor. Substitution of Gly8 with the more flexible residue beta-Ala8 increases its selectivity with respect to other two known receptors (NK-1 and NK-3), whereas substitution with either D-Ala8 or GABA8 deprives the peptide of its biological activity. These findings can be interpreted by a conformational analysis based on NMR studies in DMSO-d6 and in a DMSO-d6/H2O cryoprotective mixture combined with internal energy calculations. NKA(4-10) is characterized by a structure containing a type I beta-turn extending from Ser5 to Gly8, followed by a gamma-turn centered on Gly8, whereas for [beta-Ala8]NKA(4-10) is possible to suggest a type I beta-turn extending from Ser5 to beta-Ala8, followed by a C8 turn comprising beta-Ala8 and Leu9 and by another beta-turn extending from beta-Ala8 to the terminal NH2. The preferred conformation of [beta-Ala8]NKA(4-10) is not compatible with models for NK-1 and NK-3 agonists proposed on the basis of rigid peptide agonists [Levian-Teitelbaum et al. (1989) Biopolymers 28, 51-64; Sumner & Ferretti (1989) FEBS Lett. 253, 117-120]. The preferred solution conformation of [beta-Ala8]NKA(4-10) may thus be considered as a likely bioactive conformation for NK-2 selective peptides.
Saviano
G
G
Dipartimento di Chimica, Università di Napoli, Italy.
Temussi
P A
PA
Motta
A
A
Maggi
C A
CA
Rovero
P
P
D000595:Amino Acid Sequence; D000818:Animals; D004121:Dimethyl Sulfoxide; D006168:Guinea Pigs; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D015288:Neurokinin A / Q000031:analogs & derivatives / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry*; D011487:Protein Conformation; D011817:Rabbits; D013329:Structure-Activity Relationship
D010446:Peptide Fragments; C064218:neurokinin A (4-10), beta-Ala(8)-; D015288:Neurokinin A; C056408:neurokinin A(4-10); D004121:Dimethyl Sulfoxide