Predicting ligand-binding differences of α1 subtype and α6 subtype of GABAA receptor using molecular modeling

The GABAA receptors are pentameric combinations of seven subunit families and 16 subunit subtypes. The pharmacological and physiological properties of GABAA receptor are largely determined by the compositions of these subunits and subtype. Among the six α subtypes, the α1 and α6 subtypes are the most divergent, conferring different responsiveness to GABA. To investigate the structural mechanisms that were responsible for the different affinity of GABA to two subtypes, the three-dimensional structure models of the extracellular domain of subtype1 and subtype6 were constructed based on the crystal structure of acetylcholine-binding protein. Docking studies were further utilized to find out the differences of ligand-binding pocket that underlie the different pharmacological properties between α6 subtype and α1 subtype. The results showed Tyr157 in loop B of β3 subunit played an important role in the recognition of GABA by subtype 1 and subtype 6. Additionally, the orientation of phenol moiety of Tyr157 in α6 subtype would result in the formation of the higher number of hydrogen bonds and strong hydrophobic contact, which might be the principal cause of high affinity of GABA to α6 subtype. Moreover, the lower docked energy obtained from docking calculation of α6 subtype was consistent with the low EC50 values in vitro.