Linked Life Data

21388146

Source:http://linkedlifedata.com/resource/pubmed/id/21388146

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
14
pubmed:dateCreated
2011-4-5
pubmed:abstractText
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.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
1520-4995
pubmed:author
pubmed:issnType
Electronic
pubmed:day
12
pubmed:volume
50
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2983-93
pubmed:dateRevised
2011-10-21
pubmed:meshHeading
pubmed-meshheading:21388146-Alanine, pubmed-meshheading:21388146-Amino Acid Substitution, pubmed-meshheading:21388146-Amino Acids, pubmed-meshheading:21388146-Animals, pubmed-meshheading:21388146-Binding, Competitive, pubmed-meshheading:21388146-CHO Cells, pubmed-meshheading:21388146-Computer Simulation, pubmed-meshheading:21388146-Cricetinae, pubmed-meshheading:21388146-Cricetulus, pubmed-meshheading:21388146-Cyclic AMP, pubmed-meshheading:21388146-Dose-Response Relationship, Drug, pubmed-meshheading:21388146-Iodine Radioisotopes, pubmed-meshheading:21388146-Leucine, pubmed-meshheading:21388146-Models, Molecular, pubmed-meshheading:21388146-Mutant Proteins, pubmed-meshheading:21388146-Protein Structure, Secondary, pubmed-meshheading:21388146-Protein Structure, Tertiary, pubmed-meshheading:21388146-Radioligand Assay, pubmed-meshheading:21388146-Rats, pubmed-meshheading:21388146-Receptors, G-Protein-Coupled, pubmed-meshheading:21388146-Receptors, Gastrointestinal Hormone, pubmed-meshheading:21388146-Secretin, pubmed-meshheading:21388146-Thermodynamics
pubmed:year
2011
pubmed:articleTitle
Importance of each residue within secretin for receptor binding and biological activity.
pubmed:affiliation
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, Arizona 85259, United States.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural