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TitleSubstrate binding and inhibition mechanism of norepinephrine transporter.
Journal, issue, pagesNature, Vol. 633, Issue 8029, Page 473-479, Year 2024
Publish dateAug 14, 2024
AuthorsWenming Ji / Anran Miao / Kai Liang / Jiameng Liu / Yuhan Qi / Yue Zhou / Xinli Duan / Jixue Sun / Lipeng Lai / Jing-Xiang Wu /
PubMed AbstractNorepinephrine transporter (NET; encoded by SLC6A2) reuptakes the majority of the released noradrenaline back to the presynaptic terminals, thereby affecting the synaptic noradrenaline level. Genetic ...Norepinephrine transporter (NET; encoded by SLC6A2) reuptakes the majority of the released noradrenaline back to the presynaptic terminals, thereby affecting the synaptic noradrenaline level. Genetic mutations and dysregulation of NET are associated with a spectrum of neurological conditions in humans, making NET an important therapeutic target. However, the structure and mechanism of NET remain unclear. Here we provide cryogenic electron microscopy structures of the human NET (hNET) in three functional states-the apo state, and in states bound to the substrate meta-iodobenzylguanidine (MIBG) or the orthosteric inhibitor radafaxine. These structures were captured in an inward-facing conformation, with a tightly sealed extracellular gate and an open intracellular gate. The substrate MIBG binds at the centre of hNET. Radafaxine also occupies the substrate-binding site and might block the structural transition of hNET for inhibition. These structures provide insights into the mechanism of substrate recognition and orthosteric inhibition of hNET.
External linksNature / PubMed:39143211
MethodsEM (single particle)
Resolution2.8 - 3.04 Å
Structure data

38208

8xb2

EMDB-38208, PDB-8xb2:
Structure of radafaxine-bound state of the human Norepinephrine Transporter
Method: EM (single particle) / Resolution: 3.04 Å

38209

8xb3

EMDB-38209, PDB-8xb3:
Structural mechanism of substrate binding and inhibition of the human Norepinephrine Transporter
Method: EM (single particle) / Resolution: 2.8 Å

38210

8xb4

EMDB-38210, PDB-8xb4:
Structure of apo state of the human Norepinephrine Transporter
Method: EM (single particle) / Resolution: 2.92 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose


ChemComp, No image

ChemComp-YNT:
Unknown entry


ChemComp, No image

ChemComp-YMN:
Unknown entry

Source
  • homo sapiens (human)
  • escherichia coli k-12 (bacteria)
KeywordsTRANSPORT PROTEIN / antidepressant / bupropion / meta-iodobenzylguanidine / Radafaxin / neuroendocrine tumors / antidepression

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