title: Probing GPCR structure: adenosine and P2Y nucleotide receptors.
abstract: The adenosine receptors (ARs) provide an example of how to accurately predict ligand recognition, even prior to the availability of a crystallographic structure. Homology modeling has been used to gain structural insight, in conjunction with site-directed mutagenesis, and structure-activity relationships of small molecular ligands. Recent X-ray structures greatly improved the accuracy of knowledge of AR ligand recognition and furthermore characterized conformational changes induced by receptor activation. Now, homology modeling extends these structural insights to related GPCRs and suggests new ligand structures. This strategy is also being applied to the eight subtypes of P2Y receptors for extracellular nucleotides, which lack X-ray structures and are best modeled by homology to the CXCR4 (peptide) receptor. Neoceptors, as studied for three of the four AR subtypes, create a molecular complementarity between a mutant receptor and a chemically tailored agonist ligand to selectively enhance affinity, implying direct physical contact and thus validating docking hypotheses.
authors: Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA. kajacobs@helix.nih.gov
authors: Kenneth A
authors: KA
authors: Jacobson
authors: Stefano
authors: S
authors: Costanzi
authors: Francesca
authors: F
authors: Deflorian
mesh_terms: D000241:Adenosine / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D006801:Humans; D011687:Purines / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000378:metabolism*; D058470:Receptors, Purinergic P2Y / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D011687:Purines; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D058470:Receptors, Purinergic P2Y; D000241:Adenosine