Conformational changes in the G protein Gs induced by the beta(2) adrenergic receptor
- Authors
- Chung, Ka Young; Rasmussen, Soren G. F.; Liu, Tong; Li, Sheng; DeVree, Brian T.; Chae, Pil Seok; Calinski, Diane; Kobilka, Brian K.; Woods, Virgil L., Jr.; Sunahara, Roger K.
- Issue Date
- Sep-2011
- Publisher
- Nature Publishing Group
- Citation
- Nature, v.477, no.7366, pp.611 - U143
- Indexed
- SCIE
SCOPUS
- Journal Title
- Nature
- Volume
- 477
- Number
- 7366
- Start Page
- 611
- End Page
- U143
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/37176
- DOI
- 10.1038/nature10488
- ISSN
- 0028-0836
- Abstract
- G protein-coupled receptors represent the largest family of membrane receptors(1) that instigate signalling through nucleotide exchange on heterotrimeric G proteins. Nucleotide exchange, or more precisely, GDP dissociation from the G protein alpha-subunit, is the key step towards G protein activation and initiation of downstream signalling cascades. Despite a wealth of biochemical and biophysical studies on inactive and active conformations of several heterotrimeric G proteins, the molecular underpinnings of G protein activation remain elusive. To characterize this mechanism, we applied peptide amide hydrogen-deuterium exchange mass spectrometry to probe changes in the structure of the heterotrimeric bovine G protein, Gs (the stimulatory G protein for adenylyl cyclase) on formation of a complex with agonist-bound human beta(2) adrenergic receptor (beta(2)AR). Here we report structural links between the receptor-binding surface and the nucleotide-binding pocket of Gs that undergo higher levels of hydrogen-deuterium exchange than would be predicted from the crystal structure of the beta(2)AR-Gs complex. Together with X-ray crystallographic and electron microscopic data of the beta(2)AR-Gs complex (from refs 2, 3), we provide a rationale for a mechanism of nucleotide exchange, whereby the receptor perturbs the structure of the amino-terminal region of the alpha-subunit of Gs and consequently alters the 'P-loop' that binds the beta-phosphate in GDP. As with the Ras family of small-molecular-weight G proteins, P-loop stabilization and beta-phosphate coordination are key determinants of GDP (and GTP) binding affinity.
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