한빛사 논문
Yang Du,1,6 Nguyen Minh Duc,2,6 Søren G.F. Rasmussen,3,6 Daniel Hilger,1 Xavier Kubiak,3 Liwen Wang,4 Jennifer Bohon,4,5 Hee Ryung Kim,2 Marcin Wegrecki,3 Awuri Asuru,4 Kyung Min Jeong,2 Jeongmi Lee,2 Mark R. Chance,4,5,7 David T. Lodowski,4,7,* Brian K. Kobilka,1,7,8,* and Ka Young Chung2,7,*
1 Molecular and Cellular Physiology, School of Medicine, Stanford University, Stanford, CA 94305, USA
2 School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
3 Department of Neuroscience, University of Copenhagen, Copenhagen 2200, Denmark
4 Department of Nutrition, Center for Proteomics and Bioinformatics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
5 Case Center for Synchrotron Biosciences, Brookhaven National Laboratory, Upton, NY 11973, USA
6 These authors contributed equally
7 Senior author
8 Lead Contact
*Correspondence: David T. Lodowski, Brian K. Kobilka,Ka Young Chung
Abstract
The activation of G proteins by G protein-coupled receptors (GPCRs) underlies the majority of transmembrane signaling by hormones and neurotransmitters. Recent structures of GPCR-G protein complexes obtained by crystallography and cryoelectron microscopy (cryo-EM) reveal similar interactions between GPCRs and the alpha subunit of different G protein isoforms. While some G protein subtype-specific differences are observed, there is no clear structural explanation for G protein subtype-selectivity. All of these complexes are stabilized in the nucleotide-free state, a condition that does not exist in living cells. In an effort to better understand the structural basis of coupling specificity, we used time-resolved structural mass spectrometry techniques to investigate GPCR-G protein complex formation and G-protein activation. Our results suggest that coupling specificity is determined by one or more transient intermediate states that serve as selectivity filters and precede the formation of the stable nucleotide-free GPCR-G protein complexes observed in crystal and cryo-EM structures.
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