AI Article Synopsis

  • The study investigates the conformational properties of the pentapeptide Ser-Phe-Leu-Leu-Arg (P5) and its more potent amide derivative (P5-NH2) using proton NMR spectroscopy in dimethylsulfoxide.
  • Findings indicate that while P5 mainly adopts an extended conformation, there is also evidence of a minor curved conformer; in contrast, P5-NH2 exhibits a more stabilized cyclic structure.
  • The stronger interactions and cyclic nature of P5-NH2 may explain its higher biological potency, suggesting that a cyclic conformation is crucial for the activity of thrombin receptor agonist peptides.

Article Abstract

The conformational properties of the pentapeptide Ser-Phe-Leu-Leu-Arg (P5), a human thrombin receptor-derived sequence forming part of a tethered ligand which activates the thrombin receptor, and its more active amide derivative Ser-Phe-Leu-Leu-Arg-NH2 (P5-NH2), have been studied by proton NMR spectroscopy in dimethylsulfoxide. Measurements of nuclear Overhauser effects, performed using two-dimensional rotating frame nuclear Overhauser (ROESY) and one-dimensional nuclear Overhauser enhancement (NOE) spectroscopy, revealed that P5 exists mainly in an extended conformation. However, proton-proton 1D-NOEs between Phe C alpha H and Ser C alpha H Leu3 C alpha H and Leu3 NH, and Leu4 C alpha H and Leu4 NH, as well as between the Ser and Arg sidechains, also implicated a minor conformer for P5 having a curved backbone and a near-cyclic structure. In contrast to P5, measurements of NOEs and ROEs for P5-NH2 revealed a more stabilized cyclic structure which may account for its higher biological potency. Thus strong interresidue sequential NH (i)-NH (i + 1) interactions, as well as C-terminal carboxamide to N-terminal side-chain interactions, i.e., Arg CONH2 to Phe ring and Arg CONH2 to Ser C alpha/C beta beta', observed at lower levels of the ROESY spectrum, supported a curved backbone structure for SFLLR-NH2. Since the higher potency P5-NH2 analogue adopts predominantly a cyclic structure, a cyclic bioactive conformation for thrombin receptor agonist peptides is suggested.

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http://dx.doi.org/10.1023/a:1026342001226DOI Listing

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