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 Gln^26^. However, astressin‐amide has a well‐defined helical structure from Leu^27^ to Ile^41^ 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 Arg^35^ 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.
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