Linked Life Data

12473122

Source:http://linkedlifedata.com/resource/pubmed/id/12473122

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
24
pubmed:dateCreated
2002-12-10
pubmed:abstractText
Previous structural and mutagenesis studies indicate that the invariant alpha-amino and alpha-carboxyl groups of glutamate receptor agonists are engaged in polar interactions with oppositely charged, conserved arginine and glutamate residues in the ligand-binding domain of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. To examine the role of these residues (R507 and E727 in the GluR-D subunit) in the discrimination between agonists and antagonists, we analyzed the ligand-binding properties of homomeric GluR-D and its soluble ligand-binding domain with mutations at these positions. Filter-binding assays using [3H]AMPA, an agonist, and [3H]Ro 48-8587, a high-affinity antagonist, as radioligands revealed that even a conservative mutation at R507 (R507K) resulted in the complete loss of both agonist and antagonist binding. In contrast, a negative charge at position 727 was necessary for agonist binding, whereas the isosteric mutation, E727Q, abolished all agonist binding but retained high-affinity binding for [3H]Ro 48-8587, displaceable by 7,8-dinitroquinoxaline-2,3-dione. Competition binding studies with antagonists representing different structural classes in combination with ligand docking experiments suggest that the role of E727 is antagonist-specific, ranging from no interaction to weak electrostatic interactions involving indirect and direct hydrogen bonding with the antagonist molecule. These results underline the importance of ion pair interaction with E727 for agonist activity and suggest that an interaction with R507, but not with E727, is essential for antagonist binding.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0014-2956
pubmed:author
pubmed:issnType
Print
pubmed:volume
269
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
6261-70
pubmed:dateRevised
2007-7-23
pubmed:meshHeading
pubmed-meshheading:12473122-Animals, pubmed-meshheading:12473122-Arginine, pubmed-meshheading:12473122-Binding Sites, pubmed-meshheading:12473122-Blotting, Western, pubmed-meshheading:12473122-Cell Membrane, pubmed-meshheading:12473122-Dose-Response Relationship, Drug, pubmed-meshheading:12473122-Glutamic Acid, pubmed-meshheading:12473122-Imidazoles, pubmed-meshheading:12473122-Kinetics, pubmed-meshheading:12473122-Ligands, pubmed-meshheading:12473122-Models, Chemical, pubmed-meshheading:12473122-Models, Molecular, pubmed-meshheading:12473122-Mutagenesis, Site-Directed, pubmed-meshheading:12473122-Mutation, pubmed-meshheading:12473122-Point Mutation, pubmed-meshheading:12473122-Protein Binding, pubmed-meshheading:12473122-Protein Conformation, pubmed-meshheading:12473122-Protein Structure, Tertiary, pubmed-meshheading:12473122-Quinazolines, pubmed-meshheading:12473122-Rats, pubmed-meshheading:12473122-Receptors, Glutamate
pubmed:year
2002
pubmed:articleTitle
Determinants of antagonist binding at the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit, GluR-D. Role of the conserved arginine 507 and glutamate 727 residues.
pubmed:affiliation
Viikki Biocenter, Department of Biosciences (Division of Biochemistry) and Institute of Biotechnology, University of Helsinki, Finland.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't