Linked Life Data

10844121

Source:http://linkedlifedata.com/resource/pubmed/id/10844121

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2-3
pubmed:dateCreated
2000-8-15
pubmed:abstractText
The metabotropic glutamate receptors belong to family C of the G-protein coupled receptor superfamily. These receptors all possess large extracellular amino terminal domains, where agonist binding takes place. We have previously constructed a molecular model of the amino terminal domain of the mGlu(1) receptor based on a weak amino acid sequence similarity with a family of bacterial periplasmic binding proteins (PBPs). The residues Ser(165) and Thr(188) were demonstrated to be involved in agonist binding to the receptor. Here, we report that mutation of Arg(78) in the mGlu(1b) receptor to leucine or glutamate completely knocks out [3H]quisqualic acid binding to the receptor. The constructed mutants, R78L and R78E, have also been characterized in a inositol phosphate assay. Here, the potency of (S)-glutamic acid and (S)-quisqualic acid was reduced 1000- and 100-fold, respectively, on R78L compared to the wild type (WT) receptor. (S)-Quisqualic acid was as potent on mutant R78E as it was on R78L, whereas (S)-glutamic acid was unable to activate R78E significantly at concentrations up to 10 mM. In conclusion, Arg(78) appears to be essential for agonist binding to the mGlu(1) receptor, most likely, through the formation of an ionic bond between its positively charged side chain and the distal acid group of the agonists. Furthermore, the different impact of the two mutations on (S)-glutamic acid and (S)-quisqualic acid potencies strongly indicates that while Arg(78) appears to be a common site of interaction for the agonists, the Group I subtype selectivity of (S)-quisqualic acid is probably determined by other residues in the amino terminal domain.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0014-2999
pubmed:author
pubmed:issnType
Print
pubmed:day
2
pubmed:volume
397
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
247-53
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:10844121-Amino Acid Sequence, pubmed-meshheading:10844121-Amino Acid Substitution, pubmed-meshheading:10844121-Arginine, pubmed-meshheading:10844121-Binding, Competitive, pubmed-meshheading:10844121-Binding Sites, pubmed-meshheading:10844121-Cell Line, pubmed-meshheading:10844121-Dose-Response Relationship, Drug, pubmed-meshheading:10844121-Excitatory Amino Acid Agonists, pubmed-meshheading:10844121-Glutamic Acid, pubmed-meshheading:10844121-Humans, pubmed-meshheading:10844121-Inositol Phosphates, pubmed-meshheading:10844121-Models, Molecular, pubmed-meshheading:10844121-Molecular Sequence Data, pubmed-meshheading:10844121-Mutation, pubmed-meshheading:10844121-Protein Structure, Tertiary, pubmed-meshheading:10844121-Quisqualic Acid, pubmed-meshheading:10844121-Receptors, Metabotropic Glutamate, pubmed-meshheading:10844121-Sequence Homology, Amino Acid
pubmed:year
2000
pubmed:articleTitle
The role of Arg(78) in the metabotropic glutamate receptor mGlu(1) for agonist binding and selectivity.
pubmed:affiliation
NeuroScience PharmaBiotec Research Centre, Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, 2 Universitetsparken, DK-2100, Copenhagen, Denmark.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't