biostudies-literatureUnknown5(3)Kleinau GIn this study we wanted to gain insights into selectivity mechanisms between G-protein-coupled receptors (GPCR) and different subtypes of G-proteins. The thyrotropin receptor (TSHR) binds G-proteins promiscuously and activates both Gs (cAMP) and Gq (IP). Our goal was to dissect selectivity patterns for both pathways in the intracellular region of this receptor. We were particularly interested in the participation of poorly investigated receptor parts.We systematically investigated the amino acids of intracellular loop (ICL) 1 and helix 8 using site-directed mutagenesis alongside characterization of cAMP and IP accumulation. This approach was guided by a homology model of activated TSHR in complex with heterotrimeric Gq, using the X-ray structure of opsin with a bound G-protein peptide as aPloS onee9745https://www.ebi.ac.uk/biostudies/studies/S-EPMC2841179biostudies-literaturePrinciples and determinants of G-protein coupling by the rhodopsin-like thyrotropin receptor.PMC2841179Gonzalez JJaeschke HMueller SKleinau GWorth CLPaschke RKrause GfalsePrinciples and determinants of G-protein coupling by the rhodopsin-like thyrotropin receptor.In this study we wanted to gain insights into selectivity mechanisms between G-protein-coupled receptors (GPCR) and different subtypes of G-proteins. The thyrotropin receptor (TSHR) binds G-proteins promiscuously and activates both Gs (cAMP) and Gq (IP). Our goal was to dissect selectivity patterns for both pathways in the intracellular region of this receptor. We were particularly interested in the participation of poorly investigated receptor parts.We systematically investigated the amino acids of intracellular loop (ICL) 1 and helix 8 using site-directed mutagenesis alongside characterization of cAMP and IP accumulation. This approach was guided by a homology model of activated TSHR in complex with heterotrimeric Gq, using the X-ray structure of opsin with a bound G-protein peptide as a2010-01-01T00:00:00Z2010 Mar2025-04-19T13:27:00.556Z2019-03-26T23:07:26ZS-EPMC28411792030577910.1371/journal.pone.0009745