Peptide hormone conformational flexibility

Many peptide hormones and neurotransmitters are small, conformatlonally flexible molecules. Thus, their conformational properties are difficult to determine, and the statistical distribution of their conformations are highly dependent on the environment. Furthermore, It Is difficult to determine which. If any, of the conformations In solution are related to their biological activity at a receptor. 

Conformational restriction is a very powerful method for probing the bioactive conformations of peptides. Small peptides have many flexible torsion angles so that enormous numbers of conformations are possible in solution. For example, a simple tripeptide such as thyrotropin-releasing hormone (TRH 7) (Fig. 15.4) with six flexible bonds could have over 65,000 possible conformations. The number of potential conformers for larger peptides is enormous, and some method is needed to exclude potential conformers. Modem biophysical methods, e.g., X-ray crystallography or isotope edited nuclear magnetic resonance (NMR), (33) can be used to characterize peptide-protein interactions for soluble proteins, but most biophysical methods cannot yet determine the conformation of a ligand bound to constitutive receptors, e.g., G-protein-coupled receptors (34, 35). 

Many peptide hormones and neurotransmitters (both hereafter referred to as hormones) are short, linear, and highly flexible molecules with conformational properties that are dependent on environment. Such properties might be imagined to be valuable for the purposes for which Nature uses them, namely, as molecular switches and chemical messengers for intercellular communication and control of cellular function. In particular, conformational flexibility could be functionally important in several ways. For example, the different conformational states might be related to a number of biological properties of these peptides including ... 

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