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Cited by 612

The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.

X-ray structure of dopamine transporter elucidates antidepressant mechanism

Open access
Penmatsa, Aravind, Wang, Kevin H., Gouaux, Eric·2013·Nature
DOI 10.1038/nature12533
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Abstract

Antidepressants targeting Na+/Cl−-coupled neurotransmitter uptake define a key therapeutic strategy to treat clinical depression and neuropathic pain. However, identifying the molecular interactions that underlie the pharmacological activity of these transport inhibitors, and thus the mechanism by which the inhibitors lead to increased synaptic neurotransmitter levels, has proven elusive. Here we present the crystal structure of the Drosophila melanogaster dopamine transporter at 3.0 Å resolution bound to the tricyclic antidepressant nortriptyline. The transporter is locked in an outward-open conformation with nortriptyline wedged between transmembrane helices 1, 3, 6 and 8, blocking the transporter from binding substrate and from isomerizing to an inward-facing conformation. Although the overall structure of the dopamine transporter is similar to that of its prokaryotic relative LeuT, there are multiple distinctions, including a kink in transmembrane helix 12 halfway across the membrane bilayer, a latch-like carboxy-terminal helix that caps the cytoplasmic gate, and a cholesterol molecule wedged within a groove formed by transmembrane helices 1a, 5 and 7. Taken together, the dopamine transporter structure reveals the molecular basis for antidepressant action on sodium-coupled neurotransmitter symporters and elucidates critical elements of eukaryotic transporter structure and modulation by lipids, thus expanding our understanding of the mechanism and regulation of neurotransmitter uptake at chemical synapses.

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Metadata

Authors
Penmatsa, A., Wang, K. H., & Gouaux, E.
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2013-09-15
Volume
503
Issue
7474
Pages
85-90
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature12533
OpenAlex
W1985176332
Cited by
612
References
9
FWCI
25.69
Type
journal article
Language
en
Open access
green

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