8Y94

Structure of Apo human norepinephrine transporter NET

Summary for 8Y94

• Entry DOI: 10.2210/pdb8y94/pdb
• EMDB information: 39069
• Descriptor: Sodium-dependent noradrenaline transporter (1 entity in total)
• Functional Keywords: neurotransmitter, transporters, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 138773.09

Authors

Zhang, H.,Xu, H.E.,Jiang, Y. (deposition date: 2024-02-06, release date: 2024-05-29, Last modification date: 2024-07-03)

Primary citation

Zhang, H.,Yin, Y.L.,Dai, A.,Zhang, T.,Zhang, C.,Wu, C.,Hu, W.,He, X.,Pan, B.,Jin, S.,Yuan, Q.,Wang, M.W.,Yang, D.,Xu, H.E.,Jiang, Y.
Dimerization and antidepressant recognition at noradrenaline transporter.
Nature, 630:247-254, 2024

PubMed Abstract: The noradrenaline transporter has a pivotal role in regulating neurotransmitter balance and is crucial for normal physiology and neurobiology. Dysfunction of noradrenaline transporter has been implicated in numerous neuropsychiatric diseases, including depression and attention deficit hyperactivity disorder. Here we report cryo-electron microscopy structures of noradrenaline transporter in apo and substrate-bound forms, and as complexes with six antidepressants. The structures reveal a noradrenaline transporter dimer interface that is mediated predominantly by cholesterol and lipid molecules. The substrate noradrenaline binds deep in the central binding pocket, and its amine group interacts with a conserved aspartate residue. Our structures also provide insight into antidepressant recognition and monoamine transporter selectivity. Together, these findings advance our understanding of noradrenaline transporter regulation and inhibition, and provide templates for designing improved antidepressants to treat neuropsychiatric disorders.

PubMed: 38750358
DOI: 10.1038/s41586-024-07437-6

Experimental method

ELECTRON MICROSCOPY (3.29 Å)