Linked Life Data

15102946

Source:http://linkedlifedata.com/resource/pubmed/id/15102946

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2004-4-22
pubmed:abstractText
The structural basis of ligand affinity can be approached by studying the interactions between a drug and receptor residues; the basis for efficacy is more complex and must involve activation-associated conformational changes. We have used wild-type (WT), a constitutively active mutant (CAM), and a "constitutively inactive" mutant beta2 adrenergic receptor (beta(2)AR) to investigate changes in the binding site that accompany binding and activation. The active state (R(*)) probably involves repositioning of at least some of the agonist-contact residues, thereby optimizing their interactions with agonist and resulting in a higher affinity for agonist. A comparison of the binding affinities of a series of phenethylamine derivatives for WT revealed a remarkable synergism between the various functional groups present in epinephrine. Binding affinity was essentially unchanged with addition of beta-OH, N-CH(3), or catechol OHs to phenethylamine. In contrast, when each of these same groups was added to the appropriate compound, already containing the other two groups, to make epinephrine, the increase in affinity was quite large (60- to 120-fold). An initial interaction between two or more contacts may stabilize an intermediate conformation of beta(2)AR, R', either by altering amino acid side chain rotamer conformations or by a more global conformational change involving the repositioning of transmembrane segments. The pattern of these effects was different in the CAM in that fewer interactions were required to observe the synergistic effect, consistent with the hypothesis that the CAM mutation enriches the proportion of receptors in R(*) or in R' from which R(*) is more readily assumed.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0026-895X
pubmed:author
pubmed:issnType
Print
pubmed:volume
65
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1181-90
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
2004
pubmed:articleTitle
Synergistic contributions of the functional groups of epinephrine to its affinity and efficacy at the beta2 adrenergic receptor.
pubmed:affiliation
Department of Pharmacology, Faculty of Medicine, University of Crete, Heraklion, Greece.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't