Linked Life Data

15817484

Source:http://linkedlifedata.com/resource/pubmed/id/15817484

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
23
pubmed:dateCreated
2005-6-6
pubmed:abstractText
The beta(2) adrenergic receptor (beta(2)AR) is a prototypical family A G protein-coupled receptor (GPCR) and an excellent model system for studying the mechanism of GPCR activation. The beta(2)AR agonist binding site is well characterized, and there is a wealth of structurally related ligands with functionally diverse properties. In the present study, we use catechol (1,2-benzenediol, a structural component of catecholamine agonists) as a molecular probe to identify mechanistic differences between beta(2)AR activation by catecholamine agonists, such as isoproterenol, and by the structurally related non-catechol partial agonist salbutamol. Using biophysical and pharmacologic approaches, we show that the aromatic ring of salbutamol binds to a different site on the beta(2)AR than the aromatic ring of catecholamines. This difference is important in receptor activation as it has been hypothesized that the aromatic ring of catecholamines plays a role in triggering receptor activation through interactions with a conserved cluster of aromatic residues in the sixth transmembrane segment by a rotamer toggle switch mechanism. Our experiments indicate that the aromatic ring of salbutamol does not activate this mechanism either directly or indirectly. Moreover, the non-catechol ring of partial agonists does not interact optimally with serine residues in the fifth transmembrane helix that have been shown to play an important role in activation by catecholamines. These results demonstrate unexpected differences in binding and activation by structurally similar agonists and partial agonists. Moreover, they provide evidence that activation of a GPCR is a multistep process that can be dissected into its component parts using agonist fragments.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
10
pubmed:volume
280
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
22165-71
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed-meshheading:15817484-Albuterol, pubmed-meshheading:15817484-Animals, pubmed-meshheading:15817484-Binding Sites, pubmed-meshheading:15817484-Biochemical Phenomena, pubmed-meshheading:15817484-Biochemistry, pubmed-meshheading:15817484-Catecholamines, pubmed-meshheading:15817484-Catechols, pubmed-meshheading:15817484-Humans, pubmed-meshheading:15817484-Insects, pubmed-meshheading:15817484-Isoproterenol, pubmed-meshheading:15817484-Kinetics, pubmed-meshheading:15817484-Ligands, pubmed-meshheading:15817484-Lipids, pubmed-meshheading:15817484-Models, Biological, pubmed-meshheading:15817484-Models, Chemical, pubmed-meshheading:15817484-Models, Molecular, pubmed-meshheading:15817484-Protein Binding, pubmed-meshheading:15817484-Protein Conformation, pubmed-meshheading:15817484-Receptors, Adrenergic, beta-2, pubmed-meshheading:15817484-Receptors, G-Protein-Coupled, pubmed-meshheading:15817484-Spectrometry, Fluorescence, pubmed-meshheading:15817484-Time Factors
pubmed:year
2005
pubmed:articleTitle
Probing the beta2 adrenoceptor binding site with catechol reveals differences in binding and activation by agonists and partial agonists.
pubmed:affiliation
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 157 Beckman Circle, Stanford, CA 94305, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural