7sk2 | pdb_00007sk2

Human wildtype GABA reuptake transporter 1 in complex with tiagabine, inward-open conformation

spinqualitylabelsall models 7sk2, resolution 3.82Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7sk2 is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: TGI Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [SC6A1_HUMAN] Myoclonic-astatic epilepsy. The disease is caused by variants affecting the gene represented in this entry. Function [SC6A1_HUMAN] Terminates the action of GABA by its high affinity sodium-dependent reuptake into presynaptic terminals. Publication Abstract from PubMed gamma-Aminobutyric acid (GABA) transporter 1 (GAT1)(1) regulates neuronal excitation of the central nervous system by clearing the synaptic cleft of the inhibitory neurotransmitter GABA upon its release from synaptic vesicles. Elevating the levels of GABA in the synaptic cleft, by inhibiting GABA reuptake transporters, is an established strategy to treat neurological disorders, such as epilepsy(2). Here we determined the cryo-electron microscopy structure of full-length, wild-type human GAT1 in complex with its clinically used inhibitor tiagabine(3), with an ordered part of only 60 kDa. Our structure reveals that tiagabine locks GAT1 in the inward-open conformation, by blocking the intracellular gate of the GABA release pathway, and thus suppresses neurotransmitter uptake. Our results provide insights into the mixed-type inhibition of GAT1 by tiagabine, which is an important anticonvulsant medication. Its pharmacodynamic profile, confirmed by our experimental data, suggests initial binding of tiagabine to the substrate-binding site in the outward-open conformation, whereas our structure presents the drug stalling the transporter in the inward-open conformation, consistent with a two-step mechanism of inhibition(4). The presented structure of GAT1 gives crucial insights into the biology and pharmacology of this important neurotransmitter transporter and provides blueprints for the rational design of neuromodulators, as well as moving the boundaries of what is considered possible in single-particle cryo-electron microscopy of challenging membrane proteins. Structural basis of GABA reuptake inhibition.,Motiwala Z, Aduri NG, Shaye H, Han GW, Lam JH, Katritch V, Cherezov V, Gati C Nature. 2022 Jun 8. pii: 10.1038/s41586-022-04814-x. doi:, 10.1038/s41586-022-04814-x. PMID:35676483 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA