Linked Life Data

12145300

Source:http://linkedlifedata.com/resource/pubmed/id/12145300

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
39
pubmed:dateCreated
2002-9-23
pubmed:abstractText
Studies in many rhodopsin-like G-protein-coupled receptors are providing a general scheme of the structural processes underlying receptor activation. Microdomains in several receptors have been identified that appear to function as activation switches. However, evidence is emerging that these receptor proteins exist in multiple conformational states. To study the molecular control of this switching process, we investigated the function of a microdomain involving the conserved helix 7 tyrosine in the serotonin 5HT2C receptor. This tyrosine of the NPXXY motif was substituted for all naturally occurring amino acids. Three distinct constitutively active receptor phenotypes were found: moderate, high, and "locked-on" constitutive activity. In contrast to the activity of the other receptor mutants, the high basal signaling of the locked-on Y7.53N mutant was neither increased by agonists nor decreased by inverse agonists. The Y7.53F mutant was uncoupled. Computational modeling based on the rhodopsin crystal structure suggested that Y7.53 interacts with the conserved aromatic ring at position 7.60 in the recently identified helix 8 domain. This provided a basis for seeking revertant mutations to correct the defective function of the Y7.53F receptor. When the Y7.53F receptor was mutated at position 7.60, the wild-type phenotype was restored. These results suggest that Y7.53 and Y7.60 contribute to a common functional microdomain connecting helices 7 and 8 that influences the switching of the 5HT2C receptor among multiple active and inactive conformations.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
27
pubmed:volume
277
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
36577-84
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:12145300-Amino Acid Motifs, pubmed-meshheading:12145300-Animals, pubmed-meshheading:12145300-COS Cells, pubmed-meshheading:12145300-DNA, Complementary, pubmed-meshheading:12145300-Dose-Response Relationship, Drug, pubmed-meshheading:12145300-Enzyme Inhibitors, pubmed-meshheading:12145300-Humans, pubmed-meshheading:12145300-Indoles, pubmed-meshheading:12145300-Kinetics, pubmed-meshheading:12145300-Ligands, pubmed-meshheading:12145300-Models, Molecular, pubmed-meshheading:12145300-Mutation, pubmed-meshheading:12145300-Phenotype, pubmed-meshheading:12145300-Protein Binding, pubmed-meshheading:12145300-Protein Conformation, pubmed-meshheading:12145300-Protein Structure, Tertiary, pubmed-meshheading:12145300-Pyridines, pubmed-meshheading:12145300-Receptor, Serotonin, 5-HT2C, pubmed-meshheading:12145300-Receptors, Serotonin, pubmed-meshheading:12145300-Software, pubmed-meshheading:12145300-Time Factors, pubmed-meshheading:12145300-Transfection, pubmed-meshheading:12145300-Tyrosine
pubmed:year
2002
pubmed:articleTitle
Conserved helix 7 tyrosine acts as a multistate conformational switch in the 5HT2C receptor. Identification of a novel "locked-on" phenotype and double revertant mutations.
pubmed:affiliation
Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.