8gnk

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CryoEM structure of cytosol-facing, substrate-bound ratGAT1

Structural highlights

8gnk is a 3 chain structure with sequence from Mus musculus and Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 3.1Å
Ligands:ABU, CL, CLR, NA, NAG, PTY
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SC6A1_RAT Mediates transport of gamma-aminobutyric acid (GABA) together with sodium and chloride and is responsible for the reuptake of GABA from the synapse (PubMed:18054861, PubMed:1975955). The translocation of GABA, however, may also occur in the reverse direction leading to the release of GABA (PubMed:18054861, PubMed:21775701). The direction and magnitude of GABA transport is a consequence of the prevailing thermodynamic conditions, determined by membrane potential and the intracellular and extracellular concentrations of Na(+), Cl(-) and GABA (PubMed:18054861, PubMed:21775701). Also mediates sodium- and chloride-dependent transport of hypotaurine (By similarity).[UniProtKB:P31648][1] [2] [3]

Publication Abstract from PubMed

The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is cleared from the synaptic cleft by the sodium- and chloride-coupled GABA transporter GAT1. Inhibition of GAT1 prolongs the GABAergic signaling at the synapse and is a strategy to treat certain forms of epilepsy. In this study, we present the cryo-electron microscopy structure of Rattus norvegicus GABA transporter 1 (rGAT1) at a resolution of 3.1 A. The structure elucidation was facilitated by epitope transfer of a fragment-antigen binding (Fab) interaction site from the Drosophila dopamine transporter (dDAT) to rGAT1. The structure reveals rGAT1 in a cytosol-facing conformation, with a linear density in the primary binding site that accommodates a molecule of GABA, a displaced ion density proximal to Na site 1 and a bound chloride ion. A unique insertion in TM10 aids the formation of a compact, closed extracellular gate. Besides yielding mechanistic insights into ion and substrate recognition, our study will enable the rational design of specific antiepileptics.

Cryo-EM structure of GABA transporter 1 reveals substrate recognition and transport mechanism.,Nayak SR, Joseph D, Hofner G, Dakua A, Athreya A, Wanner KT, Kanner BI, Penmatsa A Nat Struct Mol Biol. 2023 Jul;30(7):1023-1032. doi: 10.1038/s41594-023-01011-w. , Epub 2023 Jul 3. PMID:37400654[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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References

  1. ↑ Wu Y, Wang W, Díez-Sampedro A, Richerson GB. Nonvesicular inhibitory neurotransmission via reversal of the GABA transporter GAT-1. Neuron. 2007 Dec 6;56(5):851-65. PMID:18054861 doi:10.1016/j.neuron.2007.10.021
  2. ↑ Guastella J, Nelson N, Nelson H, Czyzyk L, Keynan S, Miedel MC, Davidson N, Lester HA, Kanner BI. Cloning and expression of a rat brain GABA transporter. Science. 1990 Sep 14;249(4974):1303-6. PMID:1975955 doi:10.1126/science.1975955
  3. ↑ Bertram S, Cherubino F, Bossi E, Castagna M, Peres A. GABA reverse transport by the neuronal cotransporter GAT1: influence of internal chloride depletion. Am J Physiol Cell Physiol. 2011 Nov;301(5):C1064-73. PMID:21775701 doi:10.1152/ajpcell.00120.2011
  4. ↑ Nayak SR, Joseph D, Höfner G, Dakua A, Athreya A, Wanner KT, Kanner BI, Penmatsa A. Cryo-EM structure of GABA transporter 1 reveals substrate recognition and transport mechanism. Nat Struct Mol Biol. 2023 Jul;30(7):1023-1032. PMID:37400654 doi:10.1038/s41594-023-01011-w

Contents


PDB ID 8gnk

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