8xb4 | pdb_00008xb4

Structure of apo state of the human Norepinephrine Transporter

spinqualitylabelsall models 8xb4, resolution 2.92Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8xb4 is a 1 chain structure with sequence from Escherichia coli K-12 and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.92Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease SC6A2_HUMAN Postural orthostatic tachycardia syndrome due to NET deficiency. The disease is caused by variants affecting the gene represented in this entry. Function SC6A2_HUMAN Mediates sodium- and chloride-dependent transport of norepinephrine (also known as noradrenaline) (PubMed:2008212, PubMed:8125921). Can also mediate sodium- and chloride-dependent transport of dopamine (PubMed:11093780, PubMed:8125921). MALE_ECOLI Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides. Publication Abstract from PubMed Norepinephrine transporter (NET; encoded by SLC6A2) reuptakes the majority of the released noradrenaline back to the presynaptic terminals, thereby affecting the synaptic noradrenaline level(1). Genetic mutations and dysregulation of NET are associated with a spectrum of neurological conditions in humans, making NET an important therapeutic target(1). However, the structure and mechanism of NET remain unclear. Here we provide cryogenic electron microscopy structures of the human NET (hNET) in three functional states-the apo state, and in states bound to the substrate meta-iodobenzylguanidine (MIBG) or the orthosteric inhibitor radafaxine. These structures were captured in an inward-facing conformation, with a tightly sealed extracellular gate and an open intracellular gate. The substrate MIBG binds at the centre of hNET. Radafaxine also occupies the substrate-binding site and might block the structural transition of hNET for inhibition. These structures provide insights into the mechanism of substrate recognition and orthosteric inhibition of hNET. Substrate binding and inhibition mechanism of norepinephrine transporter.,Ji W, Miao A, Liang K, Liu J, Qi Y, Zhou Y, Duan X, Sun J, Lai L, Wu JX Nature. 2024 Aug 14. doi: 10.1038/s41586-024-07810-5. PMID:39143211 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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