Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/9779
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dc.contributor.authorRezmann-Vitti, Linda Aen
dc.contributor.authorLouis, Simon N Sen
dc.contributor.authorNero, Tracy Len
dc.contributor.authorJackman, Graham Pen
dc.contributor.authorIakovidis, Dimitrien
dc.contributor.authorMachida, Curtis Aen
dc.contributor.authorLouis, William Jen
dc.date.accessioned2015-05-15T22:59:47Z
dc.date.available2015-05-15T22:59:47Z
dc.date.issued2004-08-15en
dc.identifier.citationBiochemical Pharmacology; 68(4): 675-88en
dc.identifier.govdoc15276075en
dc.identifier.otherPUBMEDen
dc.identifier.urihttps://ahro.austin.org.au/austinjspui/handle/1/9779en
dc.description.abstractWe investigated the role of Trp(134(3.28)), Ser(190(4.57)) and Tyr(356(7.43)) in agonist binding to, and activation of, the rat beta(1)-adrenergic receptor by comparing pK(i)s and functional responses of W134A, S190A and Y356F mutant receptors to wild type, all stably expressed in CHO cells. All three mutations significantly (P < 0.05) reduced adenylyl cyclase intrinsic activity (IA) compared to wild type in response to stimulation with both (-)-isoprenaline (53-88%) and (-)-RO363 (46-61%), and there was no significant correlation either between IA or pD(2) and pK(i) (P > 0.4), suggesting that changes in pK(i) were not sufficient to explain the fall in adenylyl cyclase activity. The most pronounced reduction in affinity (126-fold, P < 0.01) was displayed by xamoterol for the Y356F mutation, suggesting that xamoterol is able to directly interact with Tyr(356(7.43)). For the other agonists, the change in pK(i) values for the mutant receptors ranged from a 20-fold decrease to a 2-fold increase compared to the wild type. In a three-dimensional model of the rat beta(1)-adrenergic receptor, Trp(134(3.28)) and Tyr(356(7.43)) form part of a hydrophobic binding pocket involving residues in transmembrane helices 1, 2, 3 and 7. Our results suggest that Trp(134(3.28)) and Tyr(356(7.43)), together with Trp(353(7.40)), are able to interact via pi-pi interactions to stabilize the extracellular ends of transmembrane helices 3 and 7. Ser(190(4.57)) appears to be involved in a hydrogen bonding network, which maintains the spatial relationship between transmembrane helices 3 and 4. These interhelical interactions suggest that the three mutated residues stabilize the active receptor state by maintaining the proper packing of their respective transmembrane helix within the helix bundle, facilitating the appropriate movement and rotation of the transmembrane regions during the activation process.en
dc.language.isoenen
dc.subject.otherAdrenergic Agonists.pharmacologyen
dc.subject.otherAmino Acid Sequenceen
dc.subject.otherAnimalsen
dc.subject.otherCHO Cellsen
dc.subject.otherCricetinaeen
dc.subject.otherCyclic AMP.metabolismen
dc.subject.otherHumansen
dc.subject.otherMolecular Sequence Dataen
dc.subject.otherMutationen
dc.subject.otherRadioligand Assayen
dc.subject.otherRatsen
dc.subject.otherReceptors, Adrenergic, beta-1.drug effects.genetics.metabolismen
dc.subject.otherSequence Homology, Amino Aciden
dc.subject.otherSerine.metabolismen
dc.subject.otherTryptophan.metabolismen
dc.subject.otherTyrosine.metabolismen
dc.titleAgonist binding and activation of the rat beta(1)-adrenergic receptor: role of Trp(134(3.28)), Ser(190(4.57)) and Tyr(356(7.43)).en
dc.typeJournal Articleen
dc.identifier.journaltitleBiochemical pharmacologyen
dc.identifier.affiliationDepartment of Medicine, Clinical Pharmacology and Therapeutics Unit, The University of Melbourne, Austin Health, Heidelberg 3084, Victoria, Australiaen
dc.identifier.doi10.1016/j.bcp.2004.04.021en
dc.description.pages675-88en
dc.relation.urlhttps://pubmed.ncbi.nlm.nih.gov/15276075en
dc.type.austinJournal Articleen
local.name.researcherLouis, William J
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.cerifentitytypePublications-
item.fulltextNo Fulltext-
item.grantfulltextnone-
item.languageiso639-1en-
item.openairetypeJournal Article-
crisitem.author.deptClinical Pharmacology and Therapeutics-
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