Importance of each residue within secretin for receptor binding and biological activity

Maoqing Dong, Angela Le, Jerez A. Te, Delia I. Pinon, Andrew J. Bordner, Laurence J Miller

Research output: Contribution to journalArticle

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Abstract

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, Leu 10, Asp15, Leu19, and Leu23. The residues most critical for biological activity included His1, Gly4, Thr7, Ser8, Glu9, Leu 10, Leu19, Leu22, and Leu23, with Asp3, Phe6, Ser11, Leu13, Asp 15, Leu26, and Val27 also contributing. While the importance of residues in positions analogous to His1, Asp 3, 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.(Figure Presented)

Original languageEnglish (US)
Pages (from-to)2983-2993
Number of pages11
JournalBiochemistry
Volume50
Issue number14
DOIs
StatePublished - Apr 12 2011

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Secretin
Bioactivity
Molecular Dynamics Simulation
Alanine
Molecular dynamics
Molecular modeling
Peptide Hormones
Computer simulation
Bicarbonates
G-Protein-Coupled Receptors
Chemical activation
secretin receptor
Peptides
Mutation
Water

ASJC Scopus subject areas

  • Biochemistry

Cite this

Importance of each residue within secretin for receptor binding and biological activity. / Dong, Maoqing; Le, Angela; Te, Jerez A.; Pinon, Delia I.; Bordner, Andrew J.; Miller, Laurence J.

In: Biochemistry, Vol. 50, No. 14, 12.04.2011, p. 2983-2993.

Research output: Contribution to journalArticle

Dong, Maoqing ; Le, Angela ; Te, Jerez A. ; Pinon, Delia I. ; Bordner, Andrew J. ; Miller, Laurence J. / Importance of each residue within secretin for receptor binding and biological activity. In: Biochemistry. 2011 ; Vol. 50, No. 14. pp. 2983-2993.
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AB - 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, Leu 10, Asp15, Leu19, and Leu23. The residues most critical for biological activity included His1, Gly4, Thr7, Ser8, Glu9, Leu 10, Leu19, Leu22, and Leu23, with Asp3, Phe6, Ser11, Leu13, Asp 15, Leu26, and Val27 also contributing. While the importance of residues in positions analogous to His1, Asp 3, 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.(Figure Presented)

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