Interrogating the Molecular Basis for Substrate Recognition in Serotonin and Dopamine Transporters with High-Affinity Substrate-Based Bivalent Ligands

Research output: Contribution to journalJournal articleResearchpeer-review

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Interrogating the Molecular Basis for Substrate Recognition in Serotonin and Dopamine Transporters with High-Affinity Substrate-Based Bivalent Ligands. / Andersen, Jacob; Ladefoged, Lucy Kate; Kristensen, Trine N Bjerre; Munro, Lachlan; Grouleff, Julie; Stuhr-Hansen, Nicolai; Kristensen, Anders S; Schiøtt, Birgit; Strømgaard, Kristian.

In: A C S Chemical Neuroscience, Vol. 7, No. 10, 19.10.2016, p. 1406-1417.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Andersen, J, Ladefoged, LK, Kristensen, TNB, Munro, L, Grouleff, J, Stuhr-Hansen, N, Kristensen, AS, Schiøtt, B & Strømgaard, K 2016, 'Interrogating the Molecular Basis for Substrate Recognition in Serotonin and Dopamine Transporters with High-Affinity Substrate-Based Bivalent Ligands', A C S Chemical Neuroscience, vol. 7, no. 10, pp. 1406-1417. https://doi.org/10.1021/acschemneuro.6b00164

APA

Andersen, J., Ladefoged, L. K., Kristensen, T. N. B., Munro, L., Grouleff, J., Stuhr-Hansen, N., ... Strømgaard, K. (2016). Interrogating the Molecular Basis for Substrate Recognition in Serotonin and Dopamine Transporters with High-Affinity Substrate-Based Bivalent Ligands. A C S Chemical Neuroscience, 7(10), 1406-1417. https://doi.org/10.1021/acschemneuro.6b00164

Vancouver

Andersen J, Ladefoged LK, Kristensen TNB, Munro L, Grouleff J, Stuhr-Hansen N et al. Interrogating the Molecular Basis for Substrate Recognition in Serotonin and Dopamine Transporters with High-Affinity Substrate-Based Bivalent Ligands. A C S Chemical Neuroscience. 2016 Oct 19;7(10):1406-1417. https://doi.org/10.1021/acschemneuro.6b00164

Author

Andersen, Jacob ; Ladefoged, Lucy Kate ; Kristensen, Trine N Bjerre ; Munro, Lachlan ; Grouleff, Julie ; Stuhr-Hansen, Nicolai ; Kristensen, Anders S ; Schiøtt, Birgit ; Strømgaard, Kristian. / Interrogating the Molecular Basis for Substrate Recognition in Serotonin and Dopamine Transporters with High-Affinity Substrate-Based Bivalent Ligands. In: A C S Chemical Neuroscience. 2016 ; Vol. 7, No. 10. pp. 1406-1417.

Bibtex

@article{2bf44a088e8643e79817ddf5d32c95a7,
title = "Interrogating the Molecular Basis for Substrate Recognition in Serotonin and Dopamine Transporters with High-Affinity Substrate-Based Bivalent Ligands",
abstract = "The transporters for the neurotransmitters serotonin and dopamine (SERT and DAT, respectively) are targets for drugs used in the treatment of mental disorders and widely used drugs of abuse. Studies of prokaryotic homologues have advanced our structural understanding of SERT and DAT, but it still remains enigmatic whether the human transporters contain one or two high-affinity substrate binding sites. We have designed and employed 24 bivalent ligands possessing a highly systematic combination of substrate moieties (serotonin and/or dopamine) and aliphatic or poly(ethylene glycol) spacers to reveal insight into substrate recognition in SERT and DAT. An optimized bivalent ligand comprising two serotonin moieties binds SERT with 3,800-fold increased affinity compared to that of serotonin, suggesting that the human transporters have two distinct substrate binding sites. We show that the bivalent ligands are inhibitors of SERT and an experimentally validated docking model suggests that the bivalent compounds bind with one substrate moiety in the central binding site (the S1 site), whereas the other substrate moiety binds in a distinct binding site (the S2 site). A systematic study of nonconserved SERT/DAT residues surrounding the proposed binding region showed that nonconserved binding site residues do not contribute to selective recognition of substrates in SERT or DAT. This study provides novel insight into the molecular basis for substrate recognition in human transporters and provides an improved foundation for the development of new drugs targeting SERT and DAT.",
author = "Jacob Andersen and Ladefoged, {Lucy Kate} and Kristensen, {Trine N Bjerre} and Lachlan Munro and Julie Grouleff and Nicolai Stuhr-Hansen and Kristensen, {Anders S} and Birgit Schi{\o}tt and Kristian Str{\o}mgaard",
year = "2016",
month = "10",
day = "19",
doi = "10.1021/acschemneuro.6b00164",
language = "English",
volume = "7",
pages = "1406--1417",
journal = "A C S Chemical Neuroscience",
issn = "1948-7193",
publisher = "American Chemical Society",
number = "10",

}

RIS

TY - JOUR

T1 - Interrogating the Molecular Basis for Substrate Recognition in Serotonin and Dopamine Transporters with High-Affinity Substrate-Based Bivalent Ligands

AU - Andersen, Jacob

AU - Ladefoged, Lucy Kate

AU - Kristensen, Trine N Bjerre

AU - Munro, Lachlan

AU - Grouleff, Julie

AU - Stuhr-Hansen, Nicolai

AU - Kristensen, Anders S

AU - Schiøtt, Birgit

AU - Strømgaard, Kristian

PY - 2016/10/19

Y1 - 2016/10/19

N2 - The transporters for the neurotransmitters serotonin and dopamine (SERT and DAT, respectively) are targets for drugs used in the treatment of mental disorders and widely used drugs of abuse. Studies of prokaryotic homologues have advanced our structural understanding of SERT and DAT, but it still remains enigmatic whether the human transporters contain one or two high-affinity substrate binding sites. We have designed and employed 24 bivalent ligands possessing a highly systematic combination of substrate moieties (serotonin and/or dopamine) and aliphatic or poly(ethylene glycol) spacers to reveal insight into substrate recognition in SERT and DAT. An optimized bivalent ligand comprising two serotonin moieties binds SERT with 3,800-fold increased affinity compared to that of serotonin, suggesting that the human transporters have two distinct substrate binding sites. We show that the bivalent ligands are inhibitors of SERT and an experimentally validated docking model suggests that the bivalent compounds bind with one substrate moiety in the central binding site (the S1 site), whereas the other substrate moiety binds in a distinct binding site (the S2 site). A systematic study of nonconserved SERT/DAT residues surrounding the proposed binding region showed that nonconserved binding site residues do not contribute to selective recognition of substrates in SERT or DAT. This study provides novel insight into the molecular basis for substrate recognition in human transporters and provides an improved foundation for the development of new drugs targeting SERT and DAT.

AB - The transporters for the neurotransmitters serotonin and dopamine (SERT and DAT, respectively) are targets for drugs used in the treatment of mental disorders and widely used drugs of abuse. Studies of prokaryotic homologues have advanced our structural understanding of SERT and DAT, but it still remains enigmatic whether the human transporters contain one or two high-affinity substrate binding sites. We have designed and employed 24 bivalent ligands possessing a highly systematic combination of substrate moieties (serotonin and/or dopamine) and aliphatic or poly(ethylene glycol) spacers to reveal insight into substrate recognition in SERT and DAT. An optimized bivalent ligand comprising two serotonin moieties binds SERT with 3,800-fold increased affinity compared to that of serotonin, suggesting that the human transporters have two distinct substrate binding sites. We show that the bivalent ligands are inhibitors of SERT and an experimentally validated docking model suggests that the bivalent compounds bind with one substrate moiety in the central binding site (the S1 site), whereas the other substrate moiety binds in a distinct binding site (the S2 site). A systematic study of nonconserved SERT/DAT residues surrounding the proposed binding region showed that nonconserved binding site residues do not contribute to selective recognition of substrates in SERT or DAT. This study provides novel insight into the molecular basis for substrate recognition in human transporters and provides an improved foundation for the development of new drugs targeting SERT and DAT.

U2 - 10.1021/acschemneuro.6b00164

DO - 10.1021/acschemneuro.6b00164

M3 - Journal article

C2 - 27425420

VL - 7

SP - 1406

EP - 1417

JO - A C S Chemical Neuroscience

JF - A C S Chemical Neuroscience

SN - 1948-7193

IS - 10

ER -

ID: 169563112