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TitleMolecular basis of human noradrenaline transporter reuptake and inhibition.
Journal, issue, pagesNature, Vol. 632, Issue 8026, Page 921-929, Year 2024
Publish dateJul 24, 2024
AuthorsJiaxin Tan / Yuan Xiao / Fang Kong / Xiaochun Zhang / Hanwen Xu / Angqi Zhu / Yiming Liu / Jianlin Lei / Boxue Tian / Yafei Yuan / Chuangye Yan /
PubMed AbstractNoradrenaline, also known as norepinephrine, has a wide range of activities and effects on most brain cell types. Its reuptake from the synaptic cleft heavily relies on the noradrenaline transporter ...Noradrenaline, also known as norepinephrine, has a wide range of activities and effects on most brain cell types. Its reuptake from the synaptic cleft heavily relies on the noradrenaline transporter (NET) located in the presynaptic membrane. Here we report the cryo-electron microscopy (cryo-EM) structures of the human NET in both its apo state and when bound to substrates or antidepressant drugs, with resolutions ranging from 2.5 Å to 3.5 Å. The two substrates, noradrenaline and dopamine, display a similar binding mode within the central substrate binding site (S1) and within a newly identified extracellular allosteric site (S2). Four distinct antidepressants, namely, atomoxetine, desipramine, bupropion and escitalopram, occupy the S1 site to obstruct substrate transport in distinct conformations. Moreover, a potassium ion was observed within sodium-binding site 1 in the structure of the NET bound to desipramine under the KCl condition. Complemented by structural-guided biochemical analyses, our studies reveal the mechanism of substrate recognition, the alternating access of NET, and elucidate the mode of action of the four antidepressants.
External linksNature / PubMed:39048818
MethodsEM (single particle)
Resolution2.5 - 3.47 Å
Structure data

EMDB-34718, PDB-8hfe:
Cryo-EM structure of human norepinephrine transporter NET in an inward-open state at resolution of 2.5 angstrom
Method: EM (single particle) / Resolution: 2.5 Å

EMDB-34719, PDB-8hff:
Cryo-EM structure of human norepinephrine transporter NET in the presence of norepinephrine in an inward-open state at resolution of 2.9 angstrom.
Method: EM (single particle) / Resolution: 2.86 Å

EMDB-34720, PDB-8hfg:
Cryo-EM structure of human norepinephrine transporter NET in the presence of dopamine in an inward-open state at resolution of 3.0 angstrom.
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-34721, PDB-8hfi:
Cryo-EM structure of human norepinephrine transporter NET in the presence of the antidepressant desipramine in an inward-open state at resolution of 2.5 angstrom.
Method: EM (single particle) / Resolution: 2.5 Å

EMDB-34722, PDB-8hfl:
Cryo-EM structure of human norepinephrine transporter NET in the presence of the antidepressant bupropion in an inward-open state at resolution of 3.0 angstrom.
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-35157, PDB-8i3v:
Cryo-EM structure of human norepinephrine transporter NET in the presence of the antidepressant escitalopram in an inward-open state at resolution of 2.85 angstrom.
Method: EM (single particle) / Resolution: 2.85 Å

EMDB-37515, PDB-8wgr:
Cryo-EM structure of inward-open state human norepinephrine transporter NET bound with antidepressant desipramine in KCl condition.
Method: EM (single particle) / Resolution: 2.75 Å

EMDB-37520, PDB-8wgx:
Cryo-EM structure of inward-open state human norepinephrine transporter NET bound with norepinephrine in nanodisc.
Method: EM (single particle) / Resolution: 3.47 Å

EMDB-39729, PDB-8z1l:
Cryo-EM structure of human norepinephrine transporter NET in the presence of the antidepressant atomoxetine in an outward-open state at resolution of 3.4 angstrom.
Method: EM (single particle) / Resolution: 3.4 Å

Chemicals

ChemComp-CL:
Unknown entry

ChemComp-HOH:
WATER

ChemComp-LNR:
L-NOREPINEPHRINE / neurotransmitter, hormone*YM

ChemComp-LDP:
L-DOPAMINE / medication*YM

ChemComp-DSM:
3-(10,11-DIHYDRO-5H-DIBENZO[B,F]AZEPIN-5-YL)-N-METHYLPROPAN-1-AMINE / antidepressant, inhibitor*YM


ChemComp, No image

ChemComp-1XR:
Unknown entry

ChemComp-68P:
(1S)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile / antidepressant, inhibitor*YM

ChemComp-K:
Unknown entry


PDB Unreleased entry

PDB-1lx4: Solution NMR Structure Of E. coli N-Ada/DNA transcription complex

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / Norepinephrine transporter / NET / SLC6A2 / norepinephrine / dopamine / neurotransmitter / desipramine / bupropion / antidepressant. / MEMBRANE PROTEIN / escitalopram / inward-open / atomoxetine

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