Structural studies highlight new routes for allosteric GPCR modulation
Recent studies described structural states of human GHRHR and de novo designed GPCR exoframe modulators targeting the dopamine D1 receptor. The findings outline new approaches for allosteric GPCR modulation and precision therapeutics.
Advances in allosteric GPCR modulation are providing new structural and functional routes for drug discovery. Recent studies mapped the structural landscape of the human Growth Hormone-Releasing Hormone Receptor (GHRHR) across multiple functional states and described GPCR exoframe modulators (GEMs), de novo designed proteins that specifically target the transmembrane domain of GPCRs.
The research on GHRHR presented a look at a Class B1 G protein-coupled receptor vital for growth and metabolism. The study utilized high-resolution cryogenic electron microscopy and molecular dynamics simulations to map the receptor's structural landscape across multiple functional states, and successfully resolved the structures of the receptor in its ligand-free active state, its state bound to a small-molecule allosteric agonist (PCO371), and its inactive state bound to a peptidic antagonist (MIA-602).
A key innovation was the discovery of how PCO371, an allosteric agonist, binds to a unique intracellular site. Unlike traditional agonists that trigger reorganization from the extracellular side, PCO371 stabilizes the active interface from within, providing a structural basis for biased signaling. The antagonist MIA-602 was found to lock the receptor in an inactive conformation by pinning a conserved HETY motif, effectively preventing the structural movements required for G protein engagement.
In a separate study, researchers developed GEMs, de novo designed proteins that specifically target the transmembrane domain of GPCRs. Using a hallucination-like design approach with three strategic structural prompts, they selected the dopamine D1 receptor as a prototypical model and systematically investigated four GEMs.
Structural studies and functional assays showed that these GEMs bind to the transmembrane domains and function as diverse allosteric modulators, including agonist-positive allosteric modulator, negative allosteric modulator and biased allosteric modulator. The ago-PAM GEM restores the activity of various D1 receptor loss-of-function mutants, suggesting a promising therapeutic target for GPCR-related disorders.
The GHRHR study said the findings provide an atomic-level template of these "on" and "off" states and pave the way for the design of precision therapeutics, including highly selective agonists to treat growth hormone deficiency and dwarfism, or potent antagonists to combat hormone-dependent tumors and acromegaly. The GEM study said the work introduces agents for allosteric GPCR modulation and highlights the potential of deep learning-based approaches in the design of function-oriented membrane proteins.