Linked Life Data

15035617

Source:http://linkedlifedata.com/resource/pubmed/id/15035617

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
2004-3-23
pubmed:abstractText
Residue 19 of parathyroid hormone (PTH) plays a unique role in the interaction process with the PTH1 receptor. A Glu(19) --> Arg(19) substitution, based on the Arg(19) of the PTH-related protein (PTHrP), increases the binding affinity when incorporated into the N-terminus of PTH [i.e., PTH(1-20)] and has no effect when introduced into the C-terminus of PTH [i.e., PTH(15-31)]. To explore Arg(19) and the midregion (residues 10-15), we designed the novel PTH scaffold peptide, PG5, which has the PTH(1-9) domain linked to the PTH(15-31) segment via a pentaglycine spacer. Substitution of Glu(19) with Arg(19) in PG5 resulted in a 9-fold increase in binding affinity. Additionally, the substitution enhanced stimulated cAMP formation in cells expressing PTH1-delNt, a PTH1 receptor construct lacking most of the N-terminus, confirming that residue 19 is interacting with the juxtamembrane portion of PTH1. The binding and signaling capacities of the PG5 analogues were diminished relative to those of PTH(1-34), indicating that the residue 10-14 region of PTH provides more than just a simple linker function. To probe this further, the structural consequences of the glycine linker and its interaction with PTH1 were examined by circular dichroism, (1)H NMR, and extensive ligand/receptor molecular dynamics simulations. The structural data clearly illustrate the helix-stabilizing effect of Arg(19) substitution propagating N-terminally from position 19 to the pentaglycine linker. Overall, these studies suggest that an alpha-helix is the preferred conformation for the residue 15-20 region of PTH and that residues 10-14 are also required for full affinity and potency of the hormone.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0006-2960
pubmed:author
pubmed:issnType
Print
pubmed:day
30
pubmed:volume
43
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3459-70
pubmed:dateRevised
2011-10-13
pubmed:meshHeading
pubmed-meshheading:15035617-Amino Acid Sequence, pubmed-meshheading:15035617-Amino Acid Substitution, pubmed-meshheading:15035617-Animals, pubmed-meshheading:15035617-Arginine, pubmed-meshheading:15035617-COS Cells, pubmed-meshheading:15035617-Cattle, pubmed-meshheading:15035617-Cercopithecus aethiops, pubmed-meshheading:15035617-Circular Dichroism, pubmed-meshheading:15035617-Glutamic Acid, pubmed-meshheading:15035617-Glycine, pubmed-meshheading:15035617-Humans, pubmed-meshheading:15035617-LLC-PK1 Cells, pubmed-meshheading:15035617-Ligands, pubmed-meshheading:15035617-Models, Molecular, pubmed-meshheading:15035617-Molecular Sequence Data, pubmed-meshheading:15035617-Nuclear Magnetic Resonance, Biomolecular, pubmed-meshheading:15035617-Parathyroid Hormone, pubmed-meshheading:15035617-Peptide Fragments, pubmed-meshheading:15035617-Protein Binding, pubmed-meshheading:15035617-Protein Structure, Secondary, pubmed-meshheading:15035617-Protein Structure, Tertiary, pubmed-meshheading:15035617-Receptor, Parathyroid Hormone, Type 1, pubmed-meshheading:15035617-Receptors, Parathyroid Hormone, pubmed-meshheading:15035617-Signal Transduction, pubmed-meshheading:15035617-Swine
pubmed:year
2004
pubmed:articleTitle
Cooperative interaction of arginine-19 and the N-terminal signaling domain in the affinity and potency of parathyroid hormone.
pubmed:affiliation
Department of Molecular Pharmacology, Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.