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TitleDimerization and antidepressant recognition at noradrenaline transporter.
Journal, issue, pagesNature, Vol. 630, Issue 8015, Page 247-254, Year 2024
Publish dateMay 15, 2024
AuthorsHeng Zhang / Yu-Ling Yin / Antao Dai / Tianwei Zhang / Chao Zhang / Canrong Wu / Wen Hu / Xinheng He / Benxun Pan / Sanshan Jin / Qingning Yuan / Ming-Wei Wang / Dehua Yang / H Eric Xu / Yi Jiang /
PubMed AbstractThe noradrenaline transporter has a pivotal role in regulating neurotransmitter balance and is crucial for normal physiology and neurobiology. Dysfunction of noradrenaline transporter has been ...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.
External linksNature / PubMed:38750358
MethodsEM (single particle)
Resolution2.89 - 3.29 Å
Structure data

39064

8y8z

EMDB-39064, PDB-8y8z:
Structure of NET-Maprotiline in outward-open state
Method: EM (single particle) / Resolution: 3.29 Å

39065

8y90

EMDB-39065, PDB-8y90:
Structure of NET-Nefopam in outward-open state
Method: EM (single particle) / Resolution: 3.15 Å

39066

8y91

EMDB-39066, PDB-8y91:
Structure of NET-nomifensine in outward-open state
Method: EM (single particle) / Resolution: 3.13 Å

39067

8y92

EMDB-39067, PDB-8y92:
structure of NET-Atomoxetine in outward-open state
Method: EM (single particle) / Resolution: 3.29 Å

39068

8y93

EMDB-39068, PDB-8y93:
Structure of NET-Amitriptyline in outward-open state
Method: EM (single particle) / Resolution: 3.0 Å

39069

8y94

EMDB-39069, PDB-8y94:
Structure of Apo human norepinephrine transporter NET
Method: EM (single particle) / Resolution: 3.29 Å

39070

8y95

EMDB-39070, PDB-8y95:
Structure of NET-NE in Occluded state
Method: EM (single particle) / Resolution: 3.24 Å

39533

8yr2

EMDB-39533, PDB-8yr2:
Structure of NET-Nisoxetine in outward-open state
Method: EM (single particle) / Resolution: 2.89 Å

Chemicals

PDB-1lx3:
Unknown entry

ChemComp-NA:
Unknown entry

ChemComp-CL:
Unknown entry / Chloride

ChemComp-HOH:
WATER / Water

PDB-1lx6:
Crystal Structure of E. Coli Enoyl Reductase-NAD+ with a Bound Benzamide Inhibitor

PDB-1lx5:
Crystal Structure of the BMP7/ActRII Extracellular Domain Complex


PDB Unreleased entry

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

ChemComp-TP0:
Amitriptyline / antidepressant*YM / Amitriptyline

ChemComp-E5E:
Noradrenaline / neurotransmitter, hormone*YM / Norepinephrine

ChemComp-41U:
nisoxetine / antidepressant, inhibitor*YM / Nisoxetine

ChemComp-PIO:
[(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate

ChemComp-CLR:
CHOLESTEROL / Cholesterol

PDB-1lx7:
Structure of E. coli uridine phosphorylase at 2.0A

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN/INHIBITOR / transporter / TRANSPORT PROTEIN-INHIBITOR COMPLEX / transpoter / TRANSPORT PROTEIN / neurotransmitter / transporters / substrate

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