Journal article
Ligand-Dependent Modulation of G Protein Conformation Alters Drug Efficacy
SGB Furness, YL Liang, CJ Nowell, ML Halls, PJ Wookey, E Dal Maso, A Inoue, A Christopoulos, D Wootten, PM Sexton
Cell | CELL PRESS | Published : 2016
Abstract
© 2016 Elsevier Inc. G protein-coupled receptor (GPCR) signaling, mediated by hetero-trimeric G proteins, can be differentially controlled by agonists. At a molecular level, this is thought to occur principally via stabilization of distinct receptor conformations by individual ligands. These distinct conformations control subsequent recruitment of transducer and effector proteins. Here, we report that ligand efficacy at the calcitonin GPCR (CTR) is also correlated with ligand-dependent alterations to G protein conformation. We observe ligand-dependent differences in the sensitivity of the G protein ternary complex to disruption by GTP, due to conformational differences in the receptor-bound ..
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Awarded by Japan Science and Technology Agency
Funding Acknowledgements
This work was funded by National Health and Medical Research Council (NHMRC) Project Grant APP1061044 and NHMRC Program Grant APP1055134. P.M.S. is an NHMRC Principal Research Fellow and A.C. an NHMRC Senior Principal Research Fellow. M.L.H. is a NHMRC RD Wright Fellow (1061687). D.W. is an NHMRC Career Development Fellow. A. I. was funded by JST, PRESTO. We thank N.A. Lambert for the constructs encoding G<INF>alpha s</INF><SUP>72</SUP>:RLuc8 and G<INF>alpha s</INF><SUP>72</SUP>:mCherry and for critiquing the manuscript. We thank B.K. Kobilka for the construct encoding Nb35 and for advice on expression and purification of the CTR ternary complex from insect cells. We thank P. Zhao and J.R. Lane for discussions. We also thank J.B. Furness and M.L. Whitelaw for critiquing the manuscript.