1. Astressin-amide and astressin-acid are structurally different in dimethylsulfoxide
- Author
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Christy R. Grace, J. Gulyas, Jean Rivier, Roland Riek, and Laura A. Cervini
- Subjects
Chemistry ,Stereochemistry ,Corticotropin-Releasing Hormone ,Organic Chemistry ,Biophysics ,General Medicine ,Structural difference ,Biochemistry ,Amides ,Receptors, Corticotropin-Releasing Hormone ,Peptide Fragments ,Protein Structure, Secondary ,Biomaterials ,Crystallography ,chemistry.chemical_compound ,Structure-Activity Relationship ,Amide ,Side chain ,Humans ,Dimethyl Sulfoxide ,Nuclear Magnetic Resonance, Biomolecular ,hormones, hormone substitutes, and hormone antagonists ,Protein Binding - Abstract
The C-terminally amidated CRF antagonist astressin binds to CRF-R1 or CRF-R2 receptors with low nanomolar affinity while the corresponding astressin-acid has >100 times less affinity. To understand the role of the amide group in binding, the conformations of astressin-amide and astressin-acid were studied in DMSO using NMR techniques. The 3D NMR structures show that the backbones of both analogs prefer an α-helical conformation, with a small kink around Gln26. However, astressin-amide has a well-defined helical structure from Leu27 to Ile41 and a conformation very similar to the bioactive conformation reported by our group (Grace et al., Proc Natl Acad Sci USA 2007, 104, 4858–4863). In contrast, astressin-acid has an irregular helical conformation from Arg35 onward, including a rearrangement of the side chains in that region. This structural difference highlights the crucial role of the C-terminal amidation for stabilization of astressin's bioactive conformation. © 2007 Wiley Periodicals, Inc. Biopolymers 87: 196–205, 2007. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com
- Published
- 2007