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Title | Transport and inhibition mechanisms of the human noradrenaline transporter. |
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Journal, issue, pages | Nature, Vol. 632, Issue 8026, Page 930-937, Year 2024 |
Publish date | Jul 31, 2024 |
Authors | Tuo Hu / Zhuoya Yu / Jun Zhao / Yufei Meng / Kristine Salomon / Qinru Bai / Yiqing Wei / Jinghui Zhang / Shujing Xu / Qiuyun Dai / Rilei Yu / Bei Yang / Claus J Loland / Yan Zhao / |
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 ...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. |
External links | Nature / PubMed:39085602 |
Methods | EM (single particle) |
Resolution | 2.7 - 3.2 Å |
Structure data | EMDB-37842, PDB-8wtu: EMDB-37843, PDB-8wtv: EMDB-37844, PDB-8wtw: EMDB-37845, PDB-8wtx: EMDB-37846, PDB-8wty: |
Chemicals | ChemComp-NAG: ChemComp-NA: ChemComp-CL: ChemComp-E5E: ChemComp-HOH: ChemComp-0A1:
ChemComp-Y60:
ChemComp-XEF: |
Source |
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Keywords | STRUCTURAL PROTEIN / protein structure / Norapinephrine transporter / MrlA / noradrenaline transporter / inhibition / bupropion / Ziprasidone |