9qo9

Inward-occluded structure of human GABA transporter 3 bound to substrate GABA

spinqualitylabelsall models 9qo9, resolution 3.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9qo9 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.2Å Ligands: ABU, CL, NA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function S6A11_HUMAN Mediates sodium- and chloride-dependent transport of gamma-aminobutyric acid (GABA) (PubMed:7874447). Can also mediate transport of beta-alanine and to a lower extent that of taurine and hypotaurine (By similarity).[UniProtKB:P31650] Publication Abstract from PubMed The astrocytic gamma-aminobutyric acid (GABA) transporter, GAT3, is essential for terminating GABAergic signaling in the central nervous system. Selective inhibition of GAT3 offers a potential strategy for elevating extracellular GABA levels for the treatment of neurological disorders including epilepsy. However, few potent and selective GAT3 inhibitors have been developed, and their mechanisms of inhibition remain poorly understood. Here, we present the cryo-electron microscopy structures of full-length, wild-type human GAT3, hGAT3, bound to a selective inhibitor, to substrate GABA, or in substrate-free state. hGAT3 bound to the inhibitor or in the substrate-free state exhibits an inward-open conformation. The inhibitor binds within the intracellular permeation pathway, positioned between transmembrane helices 1, 2, 3, 6, 7, and 8. The GABA-bound hGAT3 is captured in an inward-occluded state, revealing the ion coordination and substrate recognition network, including a cation-pi interaction between GABA's gamma-amino group and a phenylalanine residue in transmembrane helix 6. Our data reveal the molecular determinants for the inhibitor selectivity, and the mode of substrate binding and transport inhibition, providing blueprints for the rational design of next-generation selective GAT3 inhibitors. Structural basis for selective inhibition of human GABA transporter GAT3.,Mortensen JS, Bavo F, Jensen MH, Pedersen APS, Storm JP, Pape T, Frolund B, Wellendorph P, Shahsavar A Nat Commun. 2026 Jan 29;17(1):1774. doi: 10.1038/s41467-026-68479-0. PMID:41611703 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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