Interplay of thermodynamics and evolution within the ternary ligand-GPCR-G protein complex

Recent studies on G protein-coupled receptors (GPCRs) dy-namics report that GPCRs adopt a wide range of conforma-tions that coexist in equilibrium, with the apo state of a GPCR having a high entropy. The formation of a ligand-GPCR-transducer complex comes with a reduction of conformational space and therefore with an entropic cost. We hypothesize that the availability of binding partners, their binding affinity and the rigidity of the respective binding sites are reflected in a distinct degree of sequence conservation to balance the energetic cost of intra-and extracellular binding events. Here, we outline the current findings in delineating the conformational space and include sequential conservation of many-to-many ligand-re-ceptor systems to discuss the entropic cost that comes with GPCR signal transduction.

Automated summary

Recent studies have shown that G protein-coupled receptors (GPCRs) can adopt various conformations that coexist in equilibrium, with the apo state possessing high entropy. The formation of a ligand-GPCR-transducer complex comes at the cost of reduced conformational space and increased entropy. This study suggests that the conservation of binding partners, their affinity, and the rigidity of binding sites are important factors in balancing the energetic cost of intra- and extracellular binding events in GPCR signal transduction.