Linked Life Data

12695525

Source:http://linkedlifedata.com/resource/pubmed/id/12695525

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2003-4-15
pubmed:abstractText
The cholecystokinin (CCK) receptors CCK1R and CCK2R exert important central and peripheral functions by binding the neuropeptide cholecystokinin. Because these receptors are potential therapeutic targets, great interest has been devoted to the identification of efficient ligands that selectively activate or inhibit these receptors. A complete mapping of the CCK binding site in these receptors would help to design new CCK ligands and to optimize their properties. In this view, a molecular model of the CCK2R occupied by CCK was built to identify CCK2R residues that interact with CCK functional groups. No such study has yet been reported for the CCK2R. Docking of CCK in the receptor was performed by taking into account our previous mutagenesis data and by using, as constraint, the direct interaction that we demonstrated between His207 in the CCK2R and Asp8 of CCK (Mol Pharmacol 54:364-371, 1998; J Biol Chem 274:23191-23197, 1999). Two residues that had not been revealed in our previous mutagenesis studies, Tyr189 (Y4.60) and Asn358 (N6.55), were identified in interaction via hydrogen bonds with the C-terminal amide of CCK, a crucial functional group of the peptide. Mutagenesis of Tyr189 (Y4.60) and Asn358 (N6.55) as well as structure-affinity studies with modified CCK analogs validated these interactions and the involvement of both residues in the CCK binding site. These results indicate that the present molecular model is an important tool to identify direct contact points between CCK and the CCK2R and to rapidly progress in mapping of the CCK2R binding site. Moreover, comparison of the present CCK2R.CCK molecular model with that of CCK1R.CCK, which we have previously published and validated, clearly argues that the positioning of CCK in these receptors is different.
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
63
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
973-82
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
2003
pubmed:articleTitle
Identification of tyrosine 189 and asparagine 358 of the cholecystokinin 2 receptor in direct interaction with the crucial C-terminal amide of cholecystokinin by molecular modeling, site-directed mutagenesis, and structure/affinity studies.
pubmed:affiliation
Institut National de la Santé et de la Recherche Médicale (INSERM) U 531, Institut Louis Bugnard, CHU Rangueil, Toulouse, France.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't