Libin Ye

Ligand-Specified Signaling Defined by Unique Transitions in G Protein Conformations

Abstract:

Despite more than a thousand GPCR structures determined by X-ray and cryo-EM, most images depict only inactive or fully active states, leading to the misconception that GPCR activation is a simple two-state (ON/OFF) flip switch. To develop a comprehensive understanding of GPCR signaling, it is essential to explore the structures, dynamics, and functions of intermediate states and their complexes. By leveraging a multi-conformational landscape visualized by ¹⁹F-qNMR for a classic GPCR—A2AR, along with a strategy to block conformational transitions, our study successfully captured intermediate states and detailed their structures in complex with heterotrimeric Gαβγ proteins. This approach also enabled functional analysis of intermediates, demonstrating that a rate-limited nucleotide exchange is initiated during formation of the intermediate GPCR-G protein complex. Furthermore, a multi-state cognate Gα conformational landscape was established using ¹⁹F-qNMR, revealing that Gα substates are not only distinctly and dynamically populated but also transition at distinct rates in response to different ligand-bound receptors. Therefore, we propose a new model that integrates quantitative G protein dynamics to explain GPCR pharmacological efficacy, emphasizing that unique multi-conformational transitions are critical determinants of signaling specificity.

Speaker: Libin Ye, University of South Florida/Moffitt Cancer Center

Dr. Libin Ye is an Associate Professor in Molecular Biosciences at the University of South Florida (USF) and is also affiliated with Moffitt Cancer Center. He earned his PhD from Nanjing Agricultural University in 2008 and received postdoctoral training at several institutions, including UIUC, the University of Pittsburgh, and the University of Toronto, before joining USF. His research focuses on developing NMR tools, particularly 19F-NMR, to dissect and quantify the conformational transitions and dynamics of G protein-coupled receptors (GPCRs) and signaling partners, and their correlations to signaling efficacies and biases. The long-term goal is to develop novel therapeutic approaches that target disease-related conformational states with minimized side effects. His lab is currently funded by NIH, DOE, and private-sector companies, including Eli Lilly and Company, to study GPCRs involved in neurodegenerative diseases, such as adenosine receptors, and in obesity, such as GLP-1R and GCGR, as well as a wave-sensitive GPCR in red tide blooms along the coast. 

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