TAILIEUCHUNG - Báo cáo khoa học: Structural and biological effects of a b2- or b3-amino acid insertion in a peptide Application to molecular recognition of substance P by the neurokinin-1 receptor

Molecular mechanics calculations on conformers of Ac-HGly-NHMe, Ac-b 2 -HAla-NHMe and Ac-b 3 -HAla-NHMe indicate that low-energy conformations of the b-amino acids backbone, corresponding to gauche rotamers around the Ca–Cbbond, may overlap canonical backbone conformers observed for a-amino acids. Therefore, Sub-stance P (SP) was used as a model peptide to analyse the structural and biological consequences of the substitution of Phe7andPhe8by(R)-b 2 -HPheandofGly9byHGly (R)-b 2 -HAla or (S)-b 3 -HAla | Eur. J. Biochem. 270 939-949 2003 FEBS 2003 doi Structural and biological effects of a p2- or b3-amino acid insertion in a peptide Application to molecular recognition of substance P by the neurokinin-1 receptor Sandrine Sagan Thierry Milcent Rachel Ponsinet Odile Convert Olivier Tasseau Gerard Chassaing Solange Lavielle and Olivier Lequin UMR 7613 CNRS-Paris 6 Universite Pierre et Marie Curie Paris France Molecular mechanics calculations on conformers of Ac-HGly-NHMe Ac-b2-HAla-NHMe and Ac-b3-HAla-NHMe indicate that low-energy conformations of the b-amino acids backbone corresponding to gauche rotamers around the Ca-Cb bond may overlap canonical backbone conformers observed for a-amino acids. Therefore Substance P SP was used as a model peptide to analyse the structural and biological consequences of the substitution of Phe7 andPhe8by R -b2-HPhe and of Gly9 by HGly R -b2-HAla or S -b3-HAla. R -b2-HAla9 SP has pharmacological potency similar to that of SP while HGly9 SP and S -b3-HAla9 SP show a 30- to 50-fold decrease in biological activities. The three analogues modified at position 9 are more resistant to degradation by angiotensin converting enzyme than SP and Ala9 SP. NMR analysis of these SP analogues suggest that a b-amino acid insertion in position 9 does not affect the overall backbone conformation. Altogether these data suggest that HGly9 SP S - b3-HAla9 SP and R -b2-HAla9 SP could adopt backbone conformations similar to that of SP Ala9 SP and Pro9 SP. In contrast incorporation of b2-HPhe in position 7 and 8 of SP led to peptides that are almost devoid of biological activity. Thus a b-amino acid could replace an a-amino acid within the sequence of a bioactive peptide provided that the additional methylene group does not cause steric hindrance and does not confine orientations of the side chain to regions of space different from those permitted in the a-amino acid. Keywords b2- and b3-amino acid secondary structure .

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