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

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

Genetically encoded photocrosslinkers locate the high-affinity binding site of antidepressant drugs in the human serotonin transporter. / Rannversson, Hafsteinn; Andersen, Jacob; Hall, Lena Sørensen; Bang-Andersen, Benny; Park, Minyoung; Huber, Thomas; Sakmar, Thomas P; Strømgaard, Kristian.

In: Nature Communications, Vol. 7, 11261, 19.04.2016, p. 1-9.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Rannversson, H, Andersen, J, Hall, LS, Bang-Andersen, B, Park, M, Huber, T, Sakmar, TP & Strømgaard, K 2016, 'Genetically encoded photocrosslinkers locate the high-affinity binding site of antidepressant drugs in the human serotonin transporter', Nature Communications, vol. 7, 11261, pp. 1-9. https://doi.org/10.1038/ncomms11261

APA

Rannversson, H., Andersen, J., Hall, L. S., Bang-Andersen, B., Park, M., Huber, T., ... Strømgaard, K. (2016). Genetically encoded photocrosslinkers locate the high-affinity binding site of antidepressant drugs in the human serotonin transporter. Nature Communications, 7, 1-9. [11261]. https://doi.org/10.1038/ncomms11261

Vancouver

Rannversson H, Andersen J, Hall LS, Bang-Andersen B, Park M, Huber T et al. Genetically encoded photocrosslinkers locate the high-affinity binding site of antidepressant drugs in the human serotonin transporter. Nature Communications. 2016 Apr 19;7:1-9. 11261. https://doi.org/10.1038/ncomms11261

Author

Rannversson, Hafsteinn ; Andersen, Jacob ; Hall, Lena Sørensen ; Bang-Andersen, Benny ; Park, Minyoung ; Huber, Thomas ; Sakmar, Thomas P ; Strømgaard, Kristian. / Genetically encoded photocrosslinkers locate the high-affinity binding site of antidepressant drugs in the human serotonin transporter. In: Nature Communications. 2016 ; Vol. 7. pp. 1-9.

Bibtex

@article{2751816f01d7481a8b22d552b884059c,
title = "Genetically encoded photocrosslinkers locate the high-affinity binding site of antidepressant drugs in the human serotonin transporter",
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.",
keywords = "Amino Acids, Antidepressive Agents, Binding Sites, Binding, Competitive, Depression, Humans, Models, Molecular, Molecular Structure, Mutation, Phenylalanine, Photochemical Processes, Protein Binding, Protein Structure, Tertiary, Serotonin Plasma Membrane Transport Proteins, Ultraviolet Rays, Journal Article, Research Support, Non-U.S. Gov't",
author = "Hafsteinn Rannversson and Jacob Andersen and Hall, {Lena S{\o}rensen} and Benny Bang-Andersen and Minyoung Park and Thomas Huber and Sakmar, {Thomas P} and Kristian Str{\o}mgaard",
year = "2016",
month = "4",
day = "19",
doi = "10.1038/ncomms11261",
language = "English",
volume = "7",
pages = "1--9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "nature publishing group",

}

RIS

TY - JOUR

T1 - Genetically encoded photocrosslinkers locate the high-affinity binding site of antidepressant drugs in the human serotonin transporter

AU - Rannversson, Hafsteinn

AU - Andersen, Jacob

AU - Hall, Lena Sørensen

AU - Bang-Andersen, Benny

AU - Park, Minyoung

AU - Huber, Thomas

AU - Sakmar, Thomas P

AU - Strømgaard, Kristian

PY - 2016/4/19

Y1 - 2016/4/19

N2 - 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.

AB - 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.

KW - Amino Acids

KW - Antidepressive Agents

KW - Binding Sites

KW - Binding, Competitive

KW - Depression

KW - Humans

KW - Models, Molecular

KW - Molecular Structure

KW - Mutation

KW - Phenylalanine

KW - Photochemical Processes

KW - Protein Binding

KW - Protein Structure, Tertiary

KW - Serotonin Plasma Membrane Transport Proteins

KW - Ultraviolet Rays

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/ncomms11261

DO - 10.1038/ncomms11261

M3 - Journal article

VL - 7

SP - 1

EP - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 11261

ER -

ID: 169437895