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Westergard, Thomas & Salari, Reza & Martin, Joseph V. & Brannigan, Grace (2015). Interactions of L-3,5,3'-Triiodothyronine, Allopregnanolone, and Ivermectin with the GABAA Receptor: Evidence for Overlapping Intersubunit Binding Modes. PLOS One, 10(9), 1-18. Retrieved from https://doi.org/doi:10.7282/T3VH5QTC

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Interactions of L-3,5,3'-Triiodothyronine, Allopregnanolone, and Ivermectin with the GABAA Receptor: Evidence for Overlapping Intersubunit Binding Modes (2015)
Thomas Westergard, Reza Salari, Joseph V. Martin, Grace Brannigan
PLOS One 10(9): 1-18.
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VersionVersion of Record (VoR)
AbstractStructural mechanisms of modulation of γ-aminobutyric acid (GABA) type A receptors by neurosteroids and hormones remain unclear. The thyroid hormone L-3,5,3’-triiodothyronine (T3) inhibits GABA-A receptors at micromolar concentrations and has common features with neurosteroids such as allopregnanolone (ALLOP). Here we use functional experiments on α2β1γ2 GABA-A receptors expressed in Xenopus oocytes to detect competitive interactions between T3 and an agonist (ivermectin, IVM) with a crystallographically determined binding site at subunit interfaces in the transmembrane domain of a homologous receptor (glutamate-gated chloride channel, GluCl). T3 and ALLOP also show competitive effects, supporting the presence of both a T3 and ALLOP binding site at one or more subunit interfaces. Molecular dynamics (MD) simulations over 200 ns are used to investigate the dynamics and energetics of T3 in the identified intersubunit sites. In these simulations, T3 molecules occupying all intersubunit sites (with the exception of the α-β interface) display numerous energetically favorable conformations with multiple hydrogen bonding partners, including previously implicated polar/acidic sidechains and a structurally conserved deformation in the M1 backbone.
Persistent URLhttps://doi.org/doi:10.7282/T3VH5QTC
SubjectsGABA-A, GABA, Thyroid hormones, Triiodothyronine, Neurosteroids, Allopregnanolone, Ivermectin
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