Stabilization of an alpha-helical conformation in an isolated hexapeptide inhibitor of calmodulin.
The conformational properties of two hexapeptides, Ac-LWRILW-NH(2) and its D-amino acid counterpart Ac-lwrilw-NH(2), identified as calmodulin inhibitors using mixture-based synthetic combinatorial library approaches, have been characterised by NMR and CD spectroscopy. The peptides fold into an alpha-helical conformation in aqueous solution. The observed short- and medium-range nuclear Overhauser effects were consistent with the formation of an alpha-helical structure and a reasonably well-defined set of structures was obtained by using restraints from the NMR data in simulated annealing calculations. Analysis of glycine-substitution analogues demonstrated that all the amino acids that make up the peptide sequence are important for the stabilization of the alpha-helical conformation. The results suggest that a well-defined set of interactions is indispensable to allow alpha-helix formation in this short hexapeptide.
Esteve
V
V
Departament de Bioquímica i Biologia Molecular, Universitat de València, E-46100 Burjassot, València, Spain.
Blondelle
S
S
Celda
B
B
Pérez-Payá
E
E
D002147:Calmodulin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002942:Circular Dichroism; D004355:Drug Stability; D006358:Hot Temperature; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008958:Models, Molecular; D009010:Monte Carlo Method; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D017433:Protein Structure, Secondary; D014461:Ultracentrifugation
D002147:Calmodulin; D010455:Peptides