Stabilization of the helical structure of Y2-selective analogues of neuropeptide Y by lactam bridges.
The importance of helical structure in an analogue of NPY selective for the Y2 receptor, Ac[Leu28,31]NPY24-36, has been investigated by introducing a lactam bridge between positions 28 and 32. The resulting analogue, Ac-cyclo28/32[Ala24,Lys28,Leu31,Glu32]NPY24-36, is a potent Y2-selective agonist. Structural analysis by NMR shows that this analogue forms a helical structure in a 40% trifluoroethanol/water mixture, whereas in water only the region around the lactam bridge (Lys28-Glu32) adopts helical-like structure, with both N- and C-termini being poorly defined. The observation of well-defined helical structure in aqueous TFE contrasts with that reported for a similar analogue, Ac-cyclo28/32[Lys28,Glu32]NPY25-36 (Rist et al. FEBS Lett. 1996, 394, 169-173), which consisted of a hairpin-like structure that brought the N- and C-termini into proximity. We have therefore determined the structures of this analogue, as well as those of Ac-cyclo28/32[Ala24,Lys28,Leu31,Glu32]NPY24-36 and Ac-cyclo28/32[Ala24,Lys28,Glu32]NPY24-36, under identical solution conditions (30% TFE/H2O mixture at 308 K) and find essentially the same helical structure in all three peptides. These findings support the proposal that these Y2-selective analogues adopt a helical structure when bound to the Y2 receptor.
Yao
Shenggen
S
Biomolecular Research Institute, 343 Royal Parade, Parkville, Victoria 3052, Australia.
Smith-White
Margaret A
MA
Potter
Erica K
EK
Norton
Raymond S
RS
D000818:Animals; D004558:Electric Stimulation; D005260:Female; D006321:Heart / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D007769:Lactams / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009478:Neuropeptide Y / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D011674:Pulse; D051381:Rats; D017208:Rats, Wistar; D017476:Receptors, Neuropeptide Y / Q000378:metabolism / Q000502:physiology*; D013329:Structure-Activity Relationship; D014630:Vagus Nerve / Q000502:physiology; D014867:Water
D007769:Lactams; D009478:Neuropeptide Y; D010456:Peptides, Cyclic; D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor; D014867:Water