Genetically encoded photocrosslinkers locate the high-affinity binding site of antidepressant drugs in the human serotonin transporter

Hafsteinn Rannversson, Jacob Andersen, Lena Sørensen, Benny Bang-Andersen, Minyoung Park, Thomas Huber, Thomas P. Sakmar and Kristian Strømgaard ()
Additional contact information
Hafsteinn Rannversson: Center for Biopharmaceuticals, University of Copenhagen
Jacob Andersen: Center for Biopharmaceuticals, University of Copenhagen
Lena Sørensen: Center for Biopharmaceuticals, University of Copenhagen
Benny Bang-Andersen: Center for Biopharmaceuticals, University of Copenhagen
Minyoung Park: Laboratory of Chemical Biology & Signal Transduction, The Rockefeller University
Thomas Huber: Laboratory of Chemical Biology & Signal Transduction, The Rockefeller University
Thomas P. Sakmar: Laboratory of Chemical Biology & Signal Transduction, The Rockefeller University
Kristian Strømgaard: Center for Biopharmaceuticals, University of Copenhagen

Nature Communications, 2016, vol. 7, issue 1, 1-9

Abstract: Abstract Despite the well-established role of the human serotonin transporter (hSERT) in the treatment of depression, the molecular details of antidepressant drug binding are still not fully understood. Here we utilize amber codon suppression in a membrane-bound transporter protein to encode photocrosslinking unnatural amino acids (UAAs) into 75 different positions in hSERT. UAAs are incorporated with high specificity, and functionally active transporters have similar transport properties and pharmacological profiles compared with wild-type transporters. We employ ultraviolet-induced crosslinking with p-azido-L-phenylalanine (azF) at selected positions in hSERT to map the binding site of imipramine, a prototypical tricyclic antidepressant, and vortioxetine, a novel multimodal antidepressant. We find that the two antidepressants crosslink with azF incorporated at different positions within the central substrate-binding site of hSERT, while no crosslinking is observed at the vestibular-binding site. Taken together, our data provide direct evidence for defining the high-affinity antidepressant binding site in hSERT.

Date: 2016
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/ncomms11261 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11261

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms11261

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().