A proton magnetic resonance study of the conformation of methionine-enkephalin as a function of pH

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Synthesis of constrained 4-(phosphonomethyl)phenylalanine derivatives as hydrolytically stable analogs of O-phosphotyrosine

International audienceIn order to elucidate the role of protein tyrosine phosphorylation involved in various intracellular signaling pathways, peptides containing O-phosphotyrosine have been developed. However, in order to improve the stability of the phosphorylated amino acid, we have designed some years ago a hydrolytically stable analogue, the 4-(phosphonomethyl)phenylalanine (Pmp). Introduced in peptide sequences, this residue, which is resistant to phosphatase action, was shown also able to inhibit substrate recognition by protein targets. With the aim to design peptidomimetics endowed with improved affinity and selectivity, we report in this study the synthesis of five new sterically hindered amino acids derived from Pmp. These modifications include α-methyl, β-methyl, β,β-dimethyl substitutions, α,β-cyclization of Pmp and methyl substitution on the phosphomomethyl group of Pmp

Preferential conformation of the endogenous opiate-like pentapeptide met-enkephalin in DMSO-d<SUB>6</SUB> solution determined by high field <SUP>1</SUP>H NMR

A preferential conformation of the endogenous opiate-like pentapeptide Met-Enkephalin in DMSO-d6 solution was proposed from high field 1H NMR experiments at variable temperature and complete analysis of the coupling constants in relation with conformational energy steric maps. This conformation is characterized by a highly folded secondary structure with a &#946;I turn involving a head-to-tail interaction and a quasi-axial position of the methionine side chain. The N-terminal Tyr-Gly moiety which exhibits a relative degree of freedom shows all the steric requirements found in opiates for a stereospecific interaction with the receptor. All these results are discussed in relation with the physicochemical and biological properties of opiate-like peptides