Kavli Affiliate: Yifan Cheng
| Authors: Maxine Bi, Xudong Wang, Jinan Wang, JUN xu, Wenkai Sun, Victtor Ayo Adediwrua, Yinglong Miao, Yifan Cheng and Libin Ye
| Summary:
Despite hundreds of GPCR-Gαβγ complex structures, these snapshots uniquely capture the fully activated complex. Consequently, a comprehensive understanding of the conformational transitions during GPCR activation and the roles of intermediate complexes in signaling remain elusive. Guided by a conformational landscape profiled by 19F quantitative NMR and Molecular Dynamics simulations, we engineered a mutant to trap an intermediate state of the adenosine A2A receptor, allowing us to determine the structure of an unliganded GPCR-Gαsβγ intermediate complex and its functionality in signal transduction. We presented direct evidence that the GPCR intermediate forms a complex with Gαsβγ and initiates a rate-limited nucleotide exchange without progressing to the fully activated end-state complex, thereby bridging a critical gap in our understanding the complexity of GPCR signaling, including efficacy and selectivity.