Influence of the replacement of amino acid by its D-enantiomer in the sequence of substance P. 2. Conformational analysis by NMR and energy calculations.
The D-enantiomer of residues 2, 4, 5, 6, 7, 8, 10 and 11 was introduced in the sequence of Substance P: Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH1. The achiral glycine was replaced by a D-Ala residue. The conformations of the D-substituted analogues were analysed by NMR and molecular energy calculations. Introduction of a D-amino acid in the address sequence of SP (1 to 5) distorted the helical structure of [D-Pro2]SP and [D-Pro4]SP. A D-glutamine in position 5 hampered the formation of an helix, the core of [D-Gln5]SP was stabilized by the presence of two beta-turns. The exact fitting of both Phe7 and Phe8 in the binding pocket can be achieved by either an alpha- or a 3(10) helix or two beta-turns types I and II'. Replacement of an amino acid in the message sequence, 6 to 11, drastically decreased the potencies of the corresponding analogues, different conformational modifications were observed. [D-Gln6]SP presented two beta-turns, however, the types of beta-turns should orientate the side-chains in such a way that [D-Gln6]SP did not fit in the binding site. The conformations of [D-Phe7]SP and [D-Phe8]SP were completely changed, a more or less extended structure being observed. Modifications in the Gly-Leu-Met-NH2 sequence did not affect the helical structure of the core of [D-Ala9]SP, [D-Leu10]SP and [D-Met11]SP, but decreased the percentage of extended structure of the C-terminal tripeptide.
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Laboratoire de Chimie Organique Structurale, CNRS URA 455, Université Pierre et Marie Curie, Paris, France.
Duplaa
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Lavielle
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Chassaing
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D000595:Amino Acid Sequence; D000596:Amino Acids / Q000032:analysis; D000818:Animals; D004285:Dogs; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D018039:Receptors, Tachykinin; D013237:Stereoisomerism; D013373:Substance P / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D015320:Tachykinins
D000596:Amino Acids; D017981:Receptors, Neurotransmitter; D018039:Receptors, Tachykinin; D015320:Tachykinins; D013373:Substance P