Structural insights into GABA transport inhibition using an engineered neurotransmitter transporter

ABSTRACT: γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter, and its levels in the synaptic space are controlled by the GABA transporter isoforms (GATs). GATs are structurally related to biogenic amine transporters but display interactions with distinct inhibitors used as anti-epileptics. In this study, we engineer the binding pocket of Drosophila melanogaster dopamine transporter to resemble GAT1 and determine high-resolution X-ray structures of the modified transporter in the substrate-free state and in complex with GAT1-inhibitors NO711 and SKF89976a that are analogues of tiagabine, a medication prescribed for the treatment of partial seizures. We observe that the primary binding site undergoes substantial shifts in subsite architecture in the modified transporter to accommodate

SUBMITTER: Ms. Deepthi Joseph 

PROVIDER: S-SCDT-EMBOJ-2022-110735 | biostudies-other |

REPOSITORIES: biostudies-other