Linked Life Data

14500738

Source:http://linkedlifedata.com/resource/pubmed/id/14500738

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2003-9-22
pubmed:abstractText
Metabotropic glutamate (mGlu) 5 is a G-protein-coupled metabotropic glutamate receptor that plays an important role as a modulator of synaptic plasticity, ion channel activity, and excitotoxicity. 2-Methyl-6-(phenylethynyl)-pyridine (MPEP) is a highly potent, noncompetitive, selective, and systemically active antagonist of mGlu5 receptors. It binds to a novel allosteric site that resides within the seven-transmembrane domain of mGlu5 receptors. Using site-directed mutagenesis, [3H]MPEP binding, a functional Ca2+ mobilization assay, and rhodopsin-based homology modeling, we identified eight residues (Pro-6543.36, Tyr-6583.40, Leu-7435.47, Thr-7806.44, Trp-7846.48, Phe-7876.51, Tyr-7916.55, and Ala-8097.47) that are crucial for MPEP-binding to rat mGlu5 receptors. Four mutations, Y6583.40V, W7846.48A, F7876.51A, and A8097.47V, caused complete loss of [3H]MPEP binding and also blocked the MPEP-mediated inhibition of quisqualate-induced intracellular Ca2+ mobilization. To visualize these experimental findings, we have constructed a homology model based on the X-ray crystal of bovine rhodopsin and have suggested a possible binding mode of MPEP. We propose that MPEP via its interactions with a network of the aromatic residues including Phe-6583.40 in transmembrane (TM) 3 helix and Trp-7986.48, Phe-7876.51, and Tyr-7916.55 in TM6 helix prevents the movement of TM6 helix relative to TM3 helix, a step that is required for receptor activation, and consequently stabilizes the inactive conformation of mGlu5 receptor. In the TM6 region, we observed a striking similarity between the critical residues involved in MPEP-binding site with those of previously identified as 1-ethyl-2-methyl-6-oxo-4-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,6-dihydropyrimidine-5-carbonitrile-binding pocket of mGlu1, pointing to a common mechanism of inhibition shared by both antagonists.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0026-895X
pubmed:author
pubmed:issnType
Print
pubmed:volume
64
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
823-32
pubmed:dateRevised
2004-11-17
pubmed:meshHeading
pubmed-meshheading:14500738-Allosteric Site, pubmed-meshheading:14500738-Amino Acid Sequence, pubmed-meshheading:14500738-Animals, pubmed-meshheading:14500738-Binding Sites, pubmed-meshheading:14500738-Calcium, pubmed-meshheading:14500738-Cells, Cultured, pubmed-meshheading:14500738-Excitatory Amino Acid Agonists, pubmed-meshheading:14500738-Excitatory Amino Acid Antagonists, pubmed-meshheading:14500738-Humans, pubmed-meshheading:14500738-Models, Molecular, pubmed-meshheading:14500738-Molecular Conformation, pubmed-meshheading:14500738-Molecular Sequence Data, pubmed-meshheading:14500738-Point Mutation, pubmed-meshheading:14500738-Protein Structure, Tertiary, pubmed-meshheading:14500738-Pyridines, pubmed-meshheading:14500738-Quisqualic Acid, pubmed-meshheading:14500738-Rats, pubmed-meshheading:14500738-Receptors, Metabotropic Glutamate, pubmed-meshheading:14500738-Rhodopsin, pubmed-meshheading:14500738-Sequence Homology, Amino Acid, pubmed-meshheading:14500738-Tritium
pubmed:year
2003
pubmed:articleTitle
Mutational analysis and molecular modeling of the binding pocket of the metabotropic glutamate 5 receptor negative modulator 2-methyl-6-(phenylethynyl)-pyridine.
pubmed:affiliation
F. Hoffmann-La Roche Ltd., PRBN-D, Bldg. 69/327, CH-4070 Basel, Switzerland. parichehr.malherbe@roche.com
pubmed:publicationType
Journal Article