Henin, Jerome; Salari, Reza; Murlidaran, Sruthi; Brannigan, Grace
A Predicted Binding Site for Cholesterol on the GABA(A) Receptor
BIOPHYSICAL JOURNAL, 106:1938-1949, MAY 6 2014

Modulation of the GABA type A receptor (GABA(A)R) function by cholesterol and other steroids is documented at the functional level, yet its structural basis is largely unknown. Current data on structurally related modulators suggest that cholesterol binds to subunit interfaces between transmembrane domains of the GABA(A)R. We construct homology models of a human GABA(A)R based on the structure of the glutamate-gated chloride channel GluCI of Caenorhabditis elegans. The models show the possibility of previously unreported disulfide bridges linking the M1 and M3 transmembrane helices in the alpha and gamma sub-units. We discuss the biological relevance of such disulfide bridges. Using our models, we investigate cholesterol binding to intersubunit cavities of the GABA(A)R transmembrane domain. We find that very similar binding modes are predicted independently by three approaches: analogy with ivermectin in the GluCI crystal structure, automated docking by AutoDock, and spontaneous rebinding events in unbiased molecular dynamics simulations. Taken together, the models and atomistic simulations suggest a somewhat flexible binding mode, with several possible orientations. Finally, we explore the possibility that cholesterol promotes pore opening through a wedge mechanism.

DOI:10.1016/j.bpj.2014.03.024

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