Synthesis, biological activity, conformational analysis by NMR and molecular modeling of N-formyl-L-Met-L-Pro-L-Phe-OMe, a proline analogue of the chemotactic peptide N-formyl-L-Met-L-Leu-L-Phe-OH.
The tripeptide N-formyl-Met-Pro-Phe-OMe (f-MPF-OMe), an analogue of the signal peptide N-formyl-Met-Leu-Phe-OH (f-MLF-OH), was synthesized and its chemotactic activity evaluated; it showed no activity in either superoxide production or calcium mobility with human neutrophils. However, the corresponding acid f-MPF-OH retained about 25% activity in the production of superoxide. The conformation of the f-MPF-OMe analogue was evaluated by NMR spectroscopy and molecular simulation and shown to predominate in a gamma-turn with a hydrogen bond between Met CO and Phe NH. Since this analogue is not chemotactic, it is suggested that for recognition the receptor prefers a peptide with a flexible backbone, favoring an extended conformation in the binding site.
Dugas
H
H
Department of Chemistry, University of Montreal, Quebec, Canada.
Laroche
M
M
Ptak
M
M
Labbé
H
H
D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism; D002630:Chemotactic Factors / Q000138:chemical synthesis / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects*; D013481:Superoxides / Q000378:metabolism
D002630:Chemotactic Factors; D013481:Superoxides; C082555:N-formylmethionyl-prolyl-phenylalanine methyl ester; D009240:N-Formylmethionine Leucyl-Phenylalanine; D002118:Calcium