TitleAnalysis of beta(2)AR-G(s) and beta(2)AR-G(i) complex formation by NMR spectroscopy
AuthorsMa, Xiuyan
Hu, Yunfei
Batebi, Hossein
Heng, Jie
Xu, Jun
Liu, Xiangyu
Niu, Xiaogang
Li, Hongwei
Hildebrand, Peter W.
Jin, Changwen
Kobilka, Brian K.
AffiliationTsinghua Univ, Beijing Adv Innovat Ctr Struct Biol, Sch Med, Beijing 100084, Peoples R China
Peking Univ, Coll Chem & Mol Engn, Beijing Nucl Magnet Resonance Ctr, Beijing 100084, Peoples R China
Chinese Acad Sci, Innovat Acad Precis Measurement Sci & Technol, Wuhan 430071, Peoples R China
Univ Leipzig, Inst Med Phys & Biophys, D-04107 Leipzig, Germany
Tsinghua Univ, Sch Pharmaceut Sci, Beijing 100084, Peoples R China
Charite Med Univ Berlin, Inst Med Phys & Biophys, Berlin, Germany
Berlin Inst Hlth, D-10178 Berlin, Germany
Stanford Univ, Dept Mol & Cellular Physiol, Sch Med, Stanford, CA 94305 USA
KeywordsSTRUCTURAL INSIGHTS
DYNAMIC PROCESS
RECEPTOR
STRATEGIES
Issue Date15-Sep-2020
PublisherPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
AbstractThe beta(2)-adrenergic receptor (beta(2)AR) is a prototypical G proteincoupled receptor (GPCR) that preferentially couples to the stimulatory G protein G(s) and stimulates cAMP formation. Functional studies have shown that the beta(2)AR also couples to inhibitory G protein G(i), activation of which inhibits cAMP formation [R. P. Xiao, Sci. STKE 2001, re15 (2001)]. A crystal structure of the beta(2)AR-G(s) complex revealed the interaction interface of beta(2)AR-G(s) and structural changes upon complex formation [S. G. Rasmussen et al., Nature 477, 549-555 (2011)], yet, the dynamic process of the beta(2)AR signaling through G(s) and its preferential coupling to G(s) over G(i) is still not fully understood. Here, we utilize solution nuclear magnetic resonance (NMR) spectroscopy and supporting molecular dynamics (MD) simulations to monitor the conformational changes in the G protein coupling interface of the beta(2)AR in response to the full agonist BI-167107 and G(s) and G(i1). These results show that BI-167107 stabilizes conformational changes in four transmembrane segments (TM4, TM5, TM6, and TM7) prior to coupling to a G protein, and that the agonist-bound receptor conformation is different from the G protein coupled state. While most of the conformational changes observed in the beta(2)AR are qualitatively the same for G(s) and G(i1), we detected distinct differences between the beta(2)AR-G(s) and the beta(2)AR-G(i1) complex in intracellular loop 2 (ICL2). Interactions with ICL2 are essential for activation of G(s). These differences between the beta(2)AR-G(s) and beta(2)AR-G(i1) complexes in ICL2 may be key determinants for G protein coupling selectivity.
URIhttp://hdl.handle.net/20.500.11897/592982
ISSN0027-8424
DOI10.1073/pnas.2009786117
IndexedSCI(E)
Appears in Collections:化学与分子工程学院

Files in This Work
There are no files associated with this item.

Web of Science®



Checked on Last Week

Scopus®



Checked on Current Time

百度学术™



Checked on Current Time

Google Scholar™





License: See PKU IR operational policies.