9KE3

Cryo-EM structure of lipid-mediated dimer of human norepinephrine transporter NET in the presence of the F3288-0031 in an inward-open state at resolution of 3.1 angstrom

This is a non-PDB format compatible entry.

Summary for 9KE3

• Entry DOI: 10.2210/pdb9ke3/pdb
• EMDB information: 62289
• Descriptor: Sodium-dependent noradrenaline transporter, (2~{S})-1-[2-methoxy-4-[(~{E})-prop-1-enyl]phenoxy]-3-[4-(phenylmethyl)piperazin-1-yl]propan-2-ol, CHOLESTEROL, ... (4 entities in total)
• Functional Keywords: complex, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 148719.20

Authors

Zhang, H.,Zhang, T.W.,Xu, E.H.,Jiang, Y. (deposition date: 2024-11-04, release date: 2025-11-19, Last modification date: 2025-12-10)

Primary citation

Zhang, H.,Zhang, T.,Wang, D.,Dai, A.,Mao, J.,Chen, Q.,Du, T.,Lu, X.,Hao, Y.,Zhang, C.,Yin, Y.L.,Hu, W.,Pan, B.,Jin, S.,Jiang, M.,Si, Y.,Yuan, Q.,Wang, M.W.,Zheng, M.,Wang, Z.,Yang, D.,Xu, H.E.,Jiang, Y.
Unveiling conformation-selective regulation of the norepinephrine transporter.
Cell, 188:6861-, 2025

PubMed Abstract: The norepinephrine transporter (NET) plays a crucial role in synaptic neurotransmission and is implicated in major depression and attention-deficit/hyperactivity disorders, yet our understanding of its allosteric, conformation-selective regulation-crucial for developing targeted therapeutics-remains limited. Through cryo-electron microscopy analysis of NET complexes with levomilnacipran, vanoxerine, and vilazodone, we identify a previously undefined allosteric site within NET's inner vestibule that enables conformation-selective regulation. This discovery introduces a "valve model," in which specific residues partition the cytoplasmic cavity into distinct chambers, determining inhibitor binding specificity. Leveraging this structural insight through virtual screening, we identify a set of inhibitors with potent NET inhibitory activity and demonstrate their antidepressant effects. Moreover, our structural identification of inhibitor occupancy at this conformation-selective site defines a mechanistic framework for targeted therapeutic intervention. These findings advance our understanding of NET allosteric modulation, providing a structure-guided framework for developing next-generation antidepressants targeting the inward-open conformation of NET for the treatment of neuropsychiatric disorders.

PubMed: 41138730
DOI: 10.1016/j.cell.2025.10.002

Experimental method

ELECTRON MICROSCOPY (3.13 Å)