9CP5
Cryo-EM structure of human GAT3, apo state, inward-open conformation
Summary for 9CP5
| Entry DOI | 10.2210/pdb9cp5/pdb |
| Related | 9CP4 |
| EMDB information | 45800 |
| Descriptor | Sodium- and chloride-dependent GABA transporter 3, 9D5 heavy chain, 9D5 light chain, ... (4 entities in total) |
| Functional Keywords | gaba transporter 3, gat3, slc6, neurotransmitter transporter, nss, cryo-em, single particle, astrocyte, membrane protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 3 |
| Total formula weight | 121102.84 |
| Authors | |
| Primary citation | Yadav, R.,Han, G.W.,Gati, C. Molecular basis of human GABA transporter 3 inhibition. Nat Commun, 16:3830-3830, 2025 Cited by PubMed Abstract: γ-Aminobutyric acid (GABA) transporters (GATs) are sodium- and chloride-dependent transporters that mediate the reuptake of the inhibitory neurotransmitter GABA after its release from synaptic vesicles. GAT3 transports GABA from the synaptic cleft into astrocytes and modulates synaptic signaling. GAT3 has been implicated in various neurological disorders and neurodegenerative diseases, rendering it a therapeutically important drug target. To understand the mechanism of transport and inhibition, here we determine cryo-electron microscopy structures of human GAT3 in its apo form and in complex with the selective inhibitor SNAP-5114. Unexpectedly, we have discovered that SNAP-5114 acts as a noncompetitive inhibitor at GAT3. SNAP-5114 binds at the orthosteric substrate binding pocket of GAT3 in its inward-open conformation, in agreement with its noncompetitive inhibition of GABA transport. In the apo state, GAT3 also adopts an inward-open conformation with the orthosteric substrate binding pocket exposed to cytoplasm, while an extensive network of interactions closes the extracellular gate. The structures, complemented with mutagenesis and radioligand uptake assays, show that the increased orthosteric substrate binding pocket volume and bulky moieties of SNAP-5114, drive the selective inhibition of GAT3 over GAT1. Our structural and functional studies reveal the mechanism of selective inhibition of GAT3 and provide a framework for GAT3-targeted rational drug design. PubMed: 40268946DOI: 10.1038/s41467-025-59066-w PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.51 Å) |
Structure validation
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