Common and Divergent Structural Features of a Series of Corticotropin Releasing Factor-Related Peptides

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• 作者：Christy Rani R. Grace ; Marilyn H. Perrin ; Jeffrey P. Cantle ; Wylie W. Vale ; Jean E. Rivier ; Roland Riek
• 刊名：Journal of the American Chemical Society
• 出版年：2007
• 出版时间：December 26, 2007
• 年：2007
• 卷：129
• 期：51
• 页码：16102 - 16114
• 全文大小：816K
• 年卷期：v.129,no.51(December 26, 2007)
• ISSN：1520-5126

文摘

Members of the corticoliberin family include the corticotropin releasing factors (CRFs), sauvagine,the urotensins, and urocortin 1 (Ucn1), which bind to both the CRF receptors CRF-R1 and CRF-R2, andthe urocortins 2 (Ucn2) and 3 (Ucn3), which are selective agonists of CRF-R2. Structure activity relationshipstudies led to several potent and long-acting analogues with selective binding to either one of the receptors.NMR structures of six ligands of this family (the antagonists astressin B and astressin₂-B, the agonistsstressin₁, and the natural ligands human Ucn1, Ucn2, and Ucn3) were determined in DMSO. These sixpeptides show differences in binding affinities, receptor-selectivity, and NMR structure. Overall, theirbackbones are -helical, with a small kink or a turn around residues 25-27, resulting in a helix-loop-helix motif. The C-terminal helices are of amphipathic nature, whereas the N-terminal helices vary in theiramphipathicity. The C-terminal helices thereby assume a conformation very similar to that of astressinbound to the ECD1 of CRF-R2 recently reported by our group.¹ On the basis of an analysis of the observed3D structures and relative potencies of [Ala]-substituted analogues, it is proposed that both helices couldplay a crucial role in receptor binding and selectivity. In conclusion, the C-terminal helices may interactalong their hydrophobic faces with the ECD1, whereas the entire N-terminal helical surface may be involvedin receptor activation. On the basis of the common and divergent features observed in the 3D structuresof these ligands, multiple binding models are proposed that may explain their plurality of actions.