Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2007-6-25
pubmed:abstractText
The P2Y11-R (P2Y11 receptor) is a less explored drug target. We computed an hP2Y11-R (human P2Y11) homology model with two templates, bovine-rhodopsin (2.6 A resolution; 1 A=0.1 nm) and a hP2Y1-ATP complex model. The hP2Y11-R model was refined using molecular dynamics calculations and validated by virtual screening methods, with an enrichment factor of 5. Furthermore, mutational analyses of Arg106, Glu186, Arg268, Arg307 and Ala313 confirmed the adequacy of our hP2Y11-R model and the computed ligand recognition mode. The E186A and R268A mutants reduced the potency of ATP by one and three orders of magnitude respectively. The R106A and R307A mutants were functionally inactive. We propose that residues Arg106, Arg268, Arg307 and Glu186 are involved in ionic interactions with the phosphate moiety of ATP. Arg307 is possibly also H-bonded to N6 of ATP via the backbone carbonyl. Activity of ATP at the F109I mutant revealed that the proposed p-stacking of Phe109 with the adenine ring is a minor interaction. The mutation A313N, which is part of a hydrophobic pocket in the vicinity of the ATP C-2 position, partially explains the high activity of 2-MeS-ATP at P2Y1-R as compared with the negligible activity at the P2Y11-R. Inactivity of ATP at the Y261A mutant implies that Tyr261 acts as a molecular switch, as in other G-protein-coupled receptors. Moreover, analysis of cAMP responses seen with the mutants showed that the efficacy of coupling of the P2Y11-R with Gs is more variable than coupling with Gq. Our model also indicates that Ser206 forms an H-bond with Pgamma (the gamma-phosphate of the triphosphate chain of ATP) and Met310 interacts with the adenine moiety.
pubmed:commentsCorrections
http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-10090736, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-10329657, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-10578132, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-10679628, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-10718337, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-10748160, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-10753868, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-10926528, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-11156592, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-11390464, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-11549687, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-11565843, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-11579443, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-11972040, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-12213051, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-12570372, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-12578987, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-12627940, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-15317452, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-15317453, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-15322289, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-15481977, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-15506957, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-16257449, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-16366591, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-16495779, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-16953187, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-17031074, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-17170198, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-4404211, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-7492540, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-7724657, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-7876172, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-7938164, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-8254673, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-8508924, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-9281613, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-9396791, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-9554879, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-9855642, http://linkedlifedata.com/resource/pubmed/commentcorrection/17338680-9881872
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
1470-8728
pubmed:author
pubmed:issnType
Electronic
pubmed:day
15
pubmed:volume
405
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
277-86
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:17338680-Adenosine Triphosphate, pubmed-meshheading:17338680-Amino Acid Sequence, pubmed-meshheading:17338680-Animals, pubmed-meshheading:17338680-Binding Sites, pubmed-meshheading:17338680-Calcium, pubmed-meshheading:17338680-Cattle, pubmed-meshheading:17338680-Computational Biology, pubmed-meshheading:17338680-DNA Mutational Analysis, pubmed-meshheading:17338680-Humans, pubmed-meshheading:17338680-Ligands, pubmed-meshheading:17338680-Models, Molecular, pubmed-meshheading:17338680-Molecular Sequence Data, pubmed-meshheading:17338680-Mutagenesis, Site-Directed, pubmed-meshheading:17338680-Purinergic P2 Receptor Agonists, pubmed-meshheading:17338680-Receptors, Purinergic P2, pubmed-meshheading:17338680-Receptors, Purinergic P2Y1, pubmed-meshheading:17338680-Rhodopsin, pubmed-meshheading:17338680-Sequence Alignment
pubmed:year
2007
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