STATIC AND DYNAMIC ROLES OF EXTRACELLULAR LOOPS IN G-PROTEIN-COUPLED RECEPTORS - A MECHANISM FOR SEQUENTIAL BINDING OF THYROTROPIN-RELEASING-HORMONE TO ITS RECEPTOR

Small ligands generally bind within the seven transmembrane-spanning h elices of G-protein-coupled receptors, but their access to the binding pocket through the closely packed loops has not been elucidated. In t his work, a model of the extracellular loops of the thyrotropin-releas ing hormone (TRH) receptor (TRHR) was constructed, and molecular dynam ics simulations and quasi-harmonic analysis have been performed to stu dy the static and dynamic roles of the extracellular domain. The stati c analysis based on curvature and electrostatic potential on the surfa ce of TRHR suggests the formation of an initial recognition site betwe en TRH and the surface of its receptor. These results are supported by experimental evidence. A quasi-harmonic analysis of the vibrations of the extracellular loops suggest that the low-frequency motions of the loops will aid the ligand to access its transmembrane binding pocket. We suggest that all small ligands may bind sequentially to the transm embrane pocket by first interacting with the surface binding site and then may be guided into the transmembrane binding pocket by fluctuatio ns in the extracellular loops.