8WTX
Cryo-EM structure of noradrenaline transporter in complex with bupropion
Summary for 8WTX
| Entry DOI | 10.2210/pdb8wtx/pdb |
| EMDB information | 37845 |
| Descriptor | Sodium-dependent noradrenaline transporter, (2~{R})-2-(~{tert}-butylamino)-1-(3-chlorophenyl)propan-1-one (2 entities in total) |
| Functional Keywords | noradrenaline transporter, inhibition, bupropion, structural protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 64040.85 |
| Authors | |
| Primary citation | Hu, T.,Yu, Z.,Zhao, J.,Meng, Y.,Salomon, K.,Bai, Q.,Wei, Y.,Zhang, J.,Xu, S.,Dai, Q.,Yu, R.,Yang, B.,Loland, C.J.,Zhao, Y. Transport and inhibition mechanisms of the human noradrenaline transporter. Nature, 632:930-937, 2024 Cited by PubMed Abstract: The noradrenaline transporter (also known as norepinephrine transporter) (NET) has a critical role in terminating noradrenergic transmission by utilizing sodium and chloride gradients to drive the reuptake of noradrenaline (also known as norepinephrine) into presynaptic neurons. It is a pharmacological target for various antidepressants and analgesic drugs. Despite decades of research, its structure and the molecular mechanisms underpinning noradrenaline transport, coupling to ion gradients and non-competitive inhibition remain unknown. Here we present high-resolution complex structures of NET in two fundamental conformations: in the apo state, and bound to the substrate noradrenaline, an analogue of the χ-conotoxin MrlA (χ-MrlA), bupropion or ziprasidone. The noradrenaline-bound structure clearly demonstrates the binding modes of noradrenaline. The coordination of Na and Cl undergoes notable alterations during conformational changes. Analysis of the structure of NET bound to χ-MrlA provides insight into how conotoxin binds allosterically and inhibits NET. Additionally, bupropion and ziprasidone stabilize NET in its inward-facing state, but they have distinct binding pockets. These structures define the mechanisms governing neurotransmitter transport and non-competitive inhibition in NET, providing a blueprint for future drug design. PubMed: 39085602DOI: 10.1038/s41586-024-07638-z PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.9 Å) |
Structure validation
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