8XB3

Structural mechanism of substrate binding and inhibition of the human Norepinephrine Transporter

Summary for 8XB3

• Entry DOI: 10.2210/pdb8xb3/pdb
• EMDB information: 38209
• Descriptor: GFP-MBP-solute carrier family 6 member 2, Iobenguane, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• Functional Keywords: meta-iodobenzylguanidine, radafaxin, neuroendocrine tumors, antidepression, transport protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 139193.31

Authors

Ji, W.M.,Wu, J.X. (deposition date: 2023-12-05, release date: 2024-06-26, Last modification date: 2024-11-20)

Primary citation

Ji, W.,Miao, A.,Liang, K.,Liu, J.,Qi, Y.,Zhou, Y.,Duan, X.,Sun, J.,Lai, L.,Wu, J.X.
Substrate binding and inhibition mechanism of norepinephrine transporter.
Nature, 633:473-479, 2024

PubMed Abstract: Norepinephrine transporter (NET; encoded by SLC6A2) reuptakes the majority of the released noradrenaline back to the presynaptic terminals, thereby affecting the synaptic noradrenaline level. Genetic mutations and dysregulation of NET are associated with a spectrum of neurological conditions in humans, making NET an important therapeutic target. 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.

PubMed: 39143211
DOI: 10.1038/s41586-024-07810-5

Experimental method

ELECTRON MICROSCOPY (2.8 Å)