Linked Life Data

11013243

Source:http://linkedlifedata.com/resource/pubmed/id/11013243

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2001-2-8
pubmed:abstractText
Peptoid antagonists are increasingly being described for G protein-coupled receptors; however, little is known about the molecular basis of their binding. Recently, the peptoid PD168368 was found to be a potent selective neuromedin B receptor (NMBR) antagonist. To investigate the molecular basis for its selectivity for the NMBR over the closely related receptor for gastrin-releasing peptide (GRPR), we used a chimeric receptor approach and a site-directed mutagenesis approach. Mutated receptors were transiently expressed in Balb 3T3. The extracellular domains of the NMBR were not important for the selectivity of PD168368. However, substitution of the 5th upper transmembrane domain (uTM5) of the NMBR by the comparable GRPR domains decreased the affinity 16-fold. When the reverse study was performed by substituting the uTM5 of NMBR into the GRPR, a 9-fold increase in affinity occurred. Each of the 4 amino acids that differed between NMBR and GRPR in the uTM5 region were exchanged, but only the substitution of Phe(220) for Tyr in the NMBR caused a decrease in affinity. When the reverse study was performed to attempt to demonstrate a gain of affinity in the GRPR, the substitution of Tyr(219) for Phe caused an increase in affinity. These results suggest that the hydroxyl group of Tyr(220) in uTM5 of NMBR plays a critical role for high selectivity of PD168368 for NMBR over GRPR. Receptor and ligand modeling suggests that the hydroxyl of the Tyr(220) interacts with nitrophenyl group of PD168368 likely primarily by hydrogen bonding. This result shows the selectivity of the peptoid PD168368, similar to that reported for numerous non-peptide analogues with other G protein-coupled receptors, is primarily dependent on interaction with transmembrane amino acids.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
5
pubmed:volume
276
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
495-504
pubmed:dateRevised
2005-11-17
pubmed:meshHeading
pubmed-meshheading:11013243-3T3 Cells, pubmed-meshheading:11013243-Amino Acid Sequence, pubmed-meshheading:11013243-Amino Acid Substitution, pubmed-meshheading:11013243-Animals, pubmed-meshheading:11013243-Binding Sites, pubmed-meshheading:11013243-Indoles, pubmed-meshheading:11013243-Mice, pubmed-meshheading:11013243-Models, Molecular, pubmed-meshheading:11013243-Molecular Sequence Data, pubmed-meshheading:11013243-Mutagenesis, Site-Directed, pubmed-meshheading:11013243-Neurokinin B, pubmed-meshheading:11013243-Peptides, pubmed-meshheading:11013243-Peptoids, pubmed-meshheading:11013243-Point Mutation, pubmed-meshheading:11013243-Protein Binding, pubmed-meshheading:11013243-Protein Conformation, pubmed-meshheading:11013243-Protein Structure, Tertiary, pubmed-meshheading:11013243-Pyridines, pubmed-meshheading:11013243-Receptors, Bombesin, pubmed-meshheading:11013243-Recombinant Fusion Proteins, pubmed-meshheading:11013243-Substrate Specificity, pubmed-meshheading:11013243-Transfection, pubmed-meshheading:11013243-Tyrosine
pubmed:year
2001
pubmed:articleTitle
Tyrosine 220 in the 5th transmembrane domain of the neuromedin B receptor is critical for the high selectivity of the peptoid antagonist PD168368.
pubmed:affiliation
Digestive Diseases Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892-1804, USA.
pubmed:publicationType
Journal Article