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1. Drug Discovery in GPCR: How to Design Drugs with Exclusive Therapeutic Effects?

Structure- and cell-based drug development systems have substantially shaped drug development landscape in the past decades.However, the components of conformational transitions and dynamics that play significant roles in signaling process are still missing in the current drug discovery system. This hinders us from completely understanding

the receptor activation and guiding us for a better drug development. Towards this, my lab proposed to delineate and quantify the conformational landscape of the GPCR using 19F-quantitative NMR (19F-qNMR), based on an emerging concept that signaling bias originates from the receptor conformational preference (Wang et al., Trend in Pharmacological Sciences, 2021). My lab explores strategies to trap or isolate individual conformational states for their functional studies in GPCR signaling beyond traditional pharmacological assessments on a global receptor. We will finally design or screen drugs that target a disease-related conformational state that leads to signaling dysfunction while minimizing or eradicating unwanted side-effects. 

In a case of studying a neurodegenerative and cardiovascular diseases-related GPCR---adenosine 2A receptor (A2AR), we were able to delineate the receptor into four conformational states at an early stage (Libin Ye., et al., et al., 2016, Nature; Libin Ye, et al., Nature Communications, 2018), including an intermediate state, serving as a landmark progress in observing the co-existing conformational states and  their  quantitative  transitions  upon  ligand  bindings  in  a  GPCR

system. Guided by MD simulation and 19F-qNMR, my lab further pushed the frontier in delineating conformational states by trapping the intermediate states in particular constructs, proposing a five-state GPCR activation model, including two inactive states (S1 and S2), two intermediate states (S3 and S4) that engage with heterotrimeric G proteins, and one fully activated state (S5) that lead to the maximal G protein signaling (Wang et al., Nature Communications, 2023). Most recently, my lab resolved the first structure of an intermediate GPCR-G protein complex in the field, though hundreds of fully activated GPCT-G protein complexes have been resolved (Bi et al., BioRxiv, 2024). The progress in understanding the structures and functions of each conformational states in GPCR signaling process will enable us to design drugs targeting on a particular conformational state to achieve a desirable therapeutic effect. 

S1-S5 state.png
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