Understanding the structure and activation mechanism of class C GPCRs: structural insights from molecular dynamics...

Class C G protein-coupled receptors (GPCRs) consititute a uniquely structured receptor family that requires dimerization and long-range conformational changes for activation. Among these, metabotropic glutamate receptors (mGluRs) and γ-aminobutyric acid type B (GABAB) receptors are key players in neurotransmission and neuromodulation; however, their activation mechanisms are not yet fully understood. This review combines insights from molecular dynamics (MD) simulations and structural studies to elucidate how these receptors activate, are allosterically regulated, and communicate between subunits. mGluRs function as homodimers, where agonist-triggered closure of the extracellular Venus flytrap (VFT) domain signals through the cysteine-rich domain (CRD) to rearrange the transmembrane domain (TMD). Conversely, GABAB receptors operate as obligate heterodimers, with distinct roles for ligand-binding and signaling subunits. MD simulations reveal that, unlike class A GPCRs, class C GPCR activation does not involve a significant outward movement of transmembrane helix 6 (TM6), suggesting a different signaling mechanism. Additionally, allosteric modulators selectively stabilize specific receptor conformations, enhancing or diminishing signaling responses. These computational insights provide a dynamic framework for understanding the function of class C GPCRs and support structure-based drug discovery for neurological and metabolic disorders.