Conformational analysis of a highly potent, constrained gonadotropin-releasing hormone antagonist. 1. Nuclear magnetic resonance

Jose Rizo-Rey, Steven C. Koerber, Rachelle J. Bienstock, Jean Rivier, Arnold T. Hagler, Lila M. Gierasch

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Abstract

Conformational analysis of a cyclic decapeptide analogue of gonadotropin-releasing hormone (GnRH) led to the design of a series of highly potent GnRH antagonists constrained by a bridge between residues 4 and 10 (Struthers, R. S.; et al. Proteins 1990, 8, 295). We have now used nuclear magnetic resonance (NMR) to study the conformational behavior of one of the most potent of these GnRH antagonists: Ac-Δ 3-Prol-D-pFPhe2-D-Trp3-c(Asp4-Tyr5-D-2Nal6-Leu7-Arg8-Pro9-Dpr10)- NH2. Our data indicates that a β-hairpin conformation within residues 5-8, stabilized by two transannular hydrogen bonds, is the best defined feature of the molecule. This structure includes a type II' β turn around positions 6 and 7, which has been proposed to be essential for the biological activity of GnRH. Conformational averaging is observed in the Asp4-Dpr10 bridge, most likely favored by the presence of two methylene groups. The linear part of the peptide, the tail formed by residues 1-3, is located above the ring and appears to be somewhat structured: a γ-turn around D-Trp3 is likely to exist, and a type II β turn around residues 1 and 2 could be frequently visited. However, some flexibility and sensitivity to the environment are evident in this region of the molecule. The β-hairpin conformation and the orientation of the tail above the ring correlate with the structure determined for the parent cyclic decapeptide, cyclo(Δ3-Prol-D-pClPhe2-D-Trp3-Ser4-Tyr5-D-Trp6-NMeLeu7-Arg8-Pro9-β- Ala10) (Baniak, E, L., II; et al. Biochemistry 1987, 26, 2642). The conformational model emerging from the NMR data, in combination with our molecular dynamics analysis (see following paper in this issue), suggests additional bridging possibilities to obtain new, more constrained GnRH antagonists.

Original languageEnglish (US)
Pages (from-to)2852-2859
Number of pages8
JournalJournal of the American Chemical Society
Volume114
Issue number8
StatePublished - 1992

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Hormone Antagonists
Gonadotropin-Releasing Hormone
Magnetic Resonance Spectroscopy
Nuclear magnetic resonance
Conformations
Dilatation and Curettage
Biochemistry
Molecules
Fourier Analysis
Molecular Dynamics Simulation
Bioactivity
Crystal orientation
Dynamic analysis
Peptides
Molecular dynamics
Hydrogen
Hydrogen bonds
Proteins

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Conformational analysis of a highly potent, constrained gonadotropin-releasing hormone antagonist. 1. Nuclear magnetic resonance. / Rizo-Rey, Jose; Koerber, Steven C.; Bienstock, Rachelle J.; Rivier, Jean; Hagler, Arnold T.; Gierasch, Lila M.

In: Journal of the American Chemical Society, Vol. 114, No. 8, 1992, p. 2852-2859.

Research output: Contribution to journalArticle

Rizo-Rey, Jose ; Koerber, Steven C. ; Bienstock, Rachelle J. ; Rivier, Jean ; Hagler, Arnold T. ; Gierasch, Lila M. / Conformational analysis of a highly potent, constrained gonadotropin-releasing hormone antagonist. 1. Nuclear magnetic resonance. In: Journal of the American Chemical Society. 1992 ; Vol. 114, No. 8. pp. 2852-2859.
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T1 - Conformational analysis of a highly potent, constrained gonadotropin-releasing hormone antagonist. 1. Nuclear magnetic resonance

AU - Rizo-Rey, Jose

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