Introduction
GPCRs transduce signals through heterotrimeric G proteins, arrestins, and associated scaffolding proteins, with coupling selectivity that varies by receptor — from NTSR1, which engages nearly all Gα subunits, to receptors with restricted coupling profiles such as 5-HT2A (Gq/11, Gz).
Allosteric modulators acting at the receptor can bias signaling toward specific transducers; a mechanistically distinct class achieves this by binding the GPCR and transducer simultaneously at the intracellular interface.
This session examines the structural basis of G protein subtype selectivity (Gi, Go, Gz) and arrestin bias, the clinical status of biased ligands at μ opioid, 5-HT2C, and D1 receptors, and the molecular glue mechanism across Class A (NTSR1/SBI-553, KOR), Class B (PTH1R/PCO371), and Class T (Tas2R14) GPCRs.
Therapeutic implications in gain- and loss-of-function contexts involving GPCR and transducer mutations are addressed. Intended for GPCR scientists, structural pharmacologists, and drug discovery professionals working on biased signaling, allosteric modulation, or transducer selectivity.
Instructor
Bryan L. Roth is the Michael Hooker Distinguished Professor of Protein Therapeutics and Translational Proteomics at the UNC School of Medicine, where his research has fundamentally advanced understanding of GPCR structure, biased signaling, and molecular pharmacology.
A member of both the National Academy of Medicine and the American Academy of Arts and Sciences, he has made seminal contributions spanning GPCR structural biology, synthetic neurobiology, and the molecular basis of psychedelic and opioid drug action.
His recent work on intracellular allosteric modulators — compounds functioning as molecular glues at the receptor–transducer interface — defines a new mechanistic paradigm for biased GPCR therapeutics and directly informs the scientific focus of this Masterclass session.
