Linked Life Data

17591774

Source:http://linkedlifedata.com/resource/pubmed/id/17591774

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
35
pubmed:dateCreated
2007-8-27
pubmed:abstractText
The second extracellular (E2) loop of G protein-coupled receptors (GPCRs) plays an essential but poorly understood role in the binding of non-peptidic small molecules. We have utilized both orthosteric ligands and allosteric modulators of the M2 muscarinic acetylcholine receptor, a prototypical Family A GPCR, to probe possible E2 loop binding dynamics. We developed a homology model based on the crystal structure of bovine rhodopsin and predicted novel cysteine substitutions that should dramatically reduce E2 loop flexibility via disulfide bond formation and significantly inhibit the binding of both types of ligands. This prediction was validated experimentally using radioligand binding, dissociation kinetics, and cell-based functional assays. The results argue for a flexible "gatekeeper" role of the E2 loop in the binding of both allosteric and orthosteric GPCR ligands.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
31
pubmed:volume
282
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
25677-86
pubmed:meshHeading
pubmed:year
2007
pubmed:articleTitle
Critical role for the second extracellular loop in the binding of both orthosteric and allosteric G protein-coupled receptor ligands.
pubmed:affiliation
Drug Discovery Biology Laboratory, Department of Pharmacology, Monash University, Clayton, 3800 Australia.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't