Analogues and fragments of secretin

König, Wolfgang; Bickel, M.; Karch, Karl; Teetz, V.; Uhmann, Rainer

doi:10.1016/0167-0115(83)90204-5

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“…Multiple secretin residues spread throughout the peptide ligand are important for binding and biological activity. This is consistent with previous studies exploring structure−activity relationships using various fragments and analogues of this hormone. ,− In these studies, binding is possible using a carboxyl-terminal fragment of secretin with truncation of up to six amino acids, but complementary addition of the amino-terminal residues to the carboxyl-terminal segment of this peptide is critical to establish high affinity binding and full agonist activity. ,− This theme is consistent for many members of this family. − …”

Section: Discussionsupporting

confidence: 87%

Importance of Each Residue within Secretin for Receptor Binding and Biological Activity

Dong

et al. 2011

Biochemistry

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Secretin is a linear 27-residue peptide hormone that stimulates pancreatic and biliary ductular bicarbonate and water secretion by acting at its family B G protein-coupled receptor. While, like other family members, the carboxyl-terminal region of secretin is most important for high affinity binding and its amino-terminal region is most important for receptor selectivity and receptor activation, determinants for these activities are distributed throughout the entire length of this peptide. In this work, we have systematically investigated changing each residue within secretin to alanine, and evaluating the impact on receptor binding and biological activity. The residues most critical for receptor binding were His1, Asp3, Gly4, Phe6, Thr7, Ser8, Leu10, Asp15, Leu19, and Leu23. The residues most critical for biological activity included His1, Gly4, Thr7, Ser8, Glu9, Leu10, Leu19, Leu22, and Leu23, with Asp3, Phe6, Ser11, Leu13, Asp15, Leu26 and Val27 also contributing. While the importance of residues in positions analogous to His1, Asp3, Phe6, Thr7, and Leu23 is conserved for several closely-related members of this family, Leu19 is uniquely important for secretin. We, therefore, have further studied this residue by molecular modeling and molecular dynamics simulations. Indeed, the molecular dynamics simulations showed that mutation of Leu19 to alanine was destabilizing, with this effect greater than that observed for the analogous position in the other close family members. This could reflect reduced contact with the receptor or an increase in the solvent-accessible surface area of the hydrophobic residues in the carboxyl terminus of secretin as bound to its receptor.

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Section: Discussionsupporting

confidence: 87%

Importance of Each Residue within Secretin for Receptor Binding and Biological Activity

Dong

et al. 2011

Biochemistry

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Analogues and fragments of secretin

Cited by 1 publication

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Importance of Each Residue within Secretin for Receptor Binding and Biological Activity

Importance of Each Residue within Secretin for Receptor Binding and Biological Activity

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