?url_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Adc&rft.title=Activation+of+G+protein-coupled+receptors+entails+cysteine+modulation+of+agonist+binding&rft.creator=Rubenstein%2C+Lester+A.&rft.creator=Lanzara%2C+Richard+G.&rft.subject=Biophysics&rft.subject=Neural+Modelling&rft.subject=Neurophysiology&rft.subject=Theoretical+Biology&rft.subject=Neuropharmacology&rft.description=The+increase+of+the+affinity+of+agonists+with+an+increase+in+pH+and+experiments+using+thiol-specific+reagents+indicate+that+G+protein-coupled+receptors+contain+an+ionizable+cysteine+residue+at+the+ligand+binding+site.+Since+treatment+of+receptors+with+reducing+agents+produces+functional+activation+and+potentiates+agonist+stimulation%2C+it+is+likely+that+this+free+sulfhydryl+modulates+receptor+activation.+We+have+derived+a+two-state+acid-base+model+for+cysteine+modulation+of+ligand+binding+which+leads+to+a+description+of+ligand+efficacy.+We+have+shown+that+pH-dependent+binding+of+agonists+is+closely+correlated+with+measurements+of+ligand+efficacy+at+the+5-HT2A+receptor.+In+general%2C+efficacy+is+determined+by+the+preference+of+a+ligand+for+the+base+of+the+receptor.+Efficacy+may+also+be+described+in+thermodynamic+terms+as+the+coupling+free+energy+involving+a+ligand+and+the+acid+and+base+states+of+the+receptor.+Molecular+modeling+of+the+third+transmembrane+domain+of+the+5-HT2A+receptor%2C+which+contains+a+conserved+cysteine%2C+shows+that+efficacy+is+determined+by+the+difference+between+the+electrostatic+interaction+energies+of+a+ligand+with+the+acid+and+base+forms+of+the+receptor+model.+The+difference+in+interaction+energy+between+the+two+forms+of+cysteine+makes+the+largest+contribution+to+this+electrostatic+interaction+energy+difference.+Therefore%2C+the+cysteine+makes+the+largest+contribution+to+ligand+efficacy.+Using+this+approach%2C+we+can+distinquish+between+the+efficacies+of+agonists+with+varying+molecular+structures+and+account+for+the+differences+between+the+properties+of+agonists+and+antagonists.&rft.publisher=Elsevier+Science&rft.contributor=Csizmadia%2C+Imre&rft.date=1998&rft.type=Journal+(Paginated)&rft.type=PeerReviewed&rft.format=application%2Fpdf&rft.identifier=http%3A%2F%2Fcogprints.org%2F4095%2F1%2FCys_Paper.pdf&rft.identifier=++Rubenstein%2C+Lester+A.+and+Lanzara%2C+Richard+G.++(1998)+Activation+of+G+protein-coupled+receptors+entails+cysteine+modulation+of+agonist+binding.++%5BJournal+(Paginated)%5D+++++&rft.relation=http%3A%2F%2Fcogprints.org%2F4095%2F