Structural flexibility of the Gas alpha-helical domain in the beta(2)-adrenoceptor Gs complex
- Authors
- Westfield, Gerwin H.; Rasmussen, Soren G. F.; Su, Min; Dutta, Somnath; DeVree, Brian T.; Chung, Ka Young; Calinski, Diane; Velez-Ruiz, Gisselle; Oleskie, Austin N.; Pardon, Els; Chae, Pil Seok; Liu, Tong; Li, Sheng; Woods, Virgil L., Jr.; Steyaert, Jan; Kobilka, Brian K.; Sunahara, Roger K.; Skiniotis, Georgios
- Issue Date
- Sep-2011
- Publisher
- National Academy of Sciences
- Keywords
- G protein-coupled receptor; negative stain electron microscopy; random conical tilt
- Citation
- Proceedings of the National Academy of Sciences of the United States of America, v.108, no.38, pp.16086 - 16091
- Indexed
- SCIE
SCOPUS
- Journal Title
- Proceedings of the National Academy of Sciences of the United States of America
- Volume
- 108
- Number
- 38
- Start Page
- 16086
- End Page
- 16091
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/37186
- DOI
- 10.1073/pnas.1113645108
- ISSN
- 0027-8424
- Abstract
- The active-state complex between an agonist-bound receptor and a guanine nucleotide-free G protein represents the fundamental signaling assembly for the majority of hormone and neurotransmitter signaling. We applied single-particle electron microscopy (EM) analysis to examine the architecture of agonist-occupied beta(2)-adrenoceptor (beta(2)AR) in complex with the heterotrimeric G protein Gs (G alpha s beta gamma). EM 2D averages and 3D reconstructions of the detergent-solubilized complex reveal an overall architecture that is in very good agreement with the crystal structure of the active-state ternary complex. Strikingly however, the alpha-helical domain of G alpha s appears highly flexible in the absence of nucleotide. In contrast, the presence of the pyrophosphate mimic foscarnet (phosphonoformate), and also the presence of GDP, favor the stabilization of the alpha-helical domain on the Ras-like domain of G alpha s. Molecular modeling of the alpha-helical domain in the 3D EM maps suggests that in its stabilized form it assumes a conformation reminiscent to the one observed in the crystal structure of G alpha s-GTP gamma S. These data argue that the alpha-helical domain undergoes a nucleotide-dependent transition from a flexible to a conformationally stabilized state.
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