8I3V

Cryo-EM structure of human norepinephrine transporter NET in the presence of the antidepressant escitalopram in an inward-open state at resolution of 2.85 angstrom.

Summary for 8I3V

• Entry DOI: 10.2210/pdb8i3v/pdb
• Related: 8HFE 8HFF 8HFG 8HFI 8HFL
• EMDB information: 35157
• Descriptor: Sodium-dependent noradrenaline transporter, (1S)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: norepinephrine, net, escitalopram, inward-open, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 69746.39

Authors

Tan, J.,Xiao, Y.,Kong, F.,Lei, J.,Yuan, Y.,Yan, C. (deposition date: 2023-01-18, release date: 2024-07-03, Last modification date: 2024-09-04)

Primary citation

Tan, J.,Xiao, Y.,Kong, F.,Zhang, X.,Xu, H.,Zhu, A.,Liu, Y.,Lei, J.,Tian, B.,Yuan, Y.,Yan, C.
Molecular basis of human noradrenaline transporter reuptake and inhibition.
Nature, 632:921-929, 2024

PubMed Abstract: Noradrenaline, also known as norepinephrine, has a wide range of activities and effects on most brain cell types. Its reuptake from the synaptic cleft heavily relies on the noradrenaline transporter (NET) located in the presynaptic membrane. Here we report the cryo-electron microscopy (cryo-EM) structures of the human NET in both its apo state and when bound to substrates or antidepressant drugs, with resolutions ranging from 2.5 Å to 3.5 Å. The two substrates, noradrenaline and dopamine, display a similar binding mode within the central substrate binding site (S1) and within a newly identified extracellular allosteric site (S2). Four distinct antidepressants, namely, atomoxetine, desipramine, bupropion and escitalopram, occupy the S1 site to obstruct substrate transport in distinct conformations. Moreover, a potassium ion was observed within sodium-binding site 1 in the structure of the NET bound to desipramine under the KCl condition. Complemented by structural-guided biochemical analyses, our studies reveal the mechanism of substrate recognition, the alternating access of NET, and elucidate the mode of action of the four antidepressants.

PubMed: 39048818
DOI: 10.1038/s41586-024-07719-z

Experimental method

ELECTRON MICROSCOPY (2.85 Å)