9cp5 | pdb_00009cp5

Cryo-EM structure of human GAT3, apo state, inward-open conformation

spinqualitylabelsall models 9cp5, resolution 3.51Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9cp5 is a 3 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.51Å Ligands: CL 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 gamma-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. Molecular basis of human GABA transporter 3 inhibition.,Yadav R, Han GW, Gati C Nat Commun. 2025 Apr 23;16(1):3830. doi: 10.1038/s41467-025-59066-w. PMID:40268946 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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