Figure 1. Asymmetric occupancy of the αβγGABA _A receptor by propofol.

( A) Photolabeling has identified interfacial binding sites for propofol (colored blobs) in the transmembrane region (seen from the extracellular view here). Furthermore, several lines of evidence now suggest that asymmetric occupancy of these sites confers a larger change in activity than symmetric occupancy (all five subunits). Click-enabled propofol analogues have confirmed asymmetric occupancy of αβγGABA _A receptor sites in their native, unperturbed state in that only α and β subunits were photoadducted. The mechanism in the case of this heteropentamer is differential affinity of the interfaces. ( B) The relationship between H-bond probability (P _hb) and affinity (pK _D) from molecular dynamic simulations shows where each interfacial binding site lies. The two γ-containing interfaces have a much lower P _hb and therefore lower affinity.