Steric hindrance mutagenesis in the conserved extracellular vestibule impedes allosteric binding of antidepressants to the serotonin transporter

Per Plenge; Lei Shi; Thijs Beuming; Jerez Te; Amy Hauck Newman; Harel Weinstein; Ulrik Gether; Claus J Loland

doi:10.1074/jbc.M112.371765

Steric hindrance mutagenesis in the conserved extracellular vestibule impedes allosteric binding of antidepressants to the serotonin transporter

Per Plenge, Lei Shi, Thijs Beuming, Jerez Te, Amy Hauck Newman, Harel Weinstein, Ulrik Gether, Claus J Loland

65 Citations (Scopus)

Abstract

Background: The serotonin transporter contains an allosteric binding site with unknown location. Results: We use molecular modeling, mutagenesis, and zinc site engineering to locate and inhibit the allosteric binding site. Conclusion: Data are consistent with the allosteric binding site being located in the extracellular vestibule. Significance: This opens the search for a new generation of antidepressant drugs directed toward the proposed allosteric binding site.

Original language	English
Journal	The Journal of Biological Chemistry
Volume	287
Issue number	47
Pages (from-to)	39316-26
Number of pages	11
ISSN	0021-9258
DOIs	https://doi.org/10.1074/jbc.M112.371765
Publication status	Published - 16 Nov 2012

Keywords

Allosteric Site
Antidepressive Agents, Second-Generation
Citalopram
Humans
Molecular Docking Simulation
Molecular Dynamics Simulation
Mutagenesis
Protein Structure, Tertiary
Serotonin Plasma Membrane Transport Proteins
Zinc

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10.1074/jbc.M112.371765

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title = "Steric hindrance mutagenesis in the conserved extracellular vestibule impedes allosteric binding of antidepressants to the serotonin transporter",

abstract = "Background: The serotonin transporter contains an allosteric binding site with unknown location. Results: We use molecular modeling, mutagenesis, and zinc site engineering to locate and inhibit the allosteric binding site. Conclusion: Data are consistent with the allosteric binding site being located in the extracellular vestibule. Significance: This opens the search for a new generation of antidepressant drugs directed toward the proposed allosteric binding site.",

keywords = "Allosteric Site, Antidepressive Agents, Second-Generation, Citalopram, Humans, Molecular Docking Simulation, Molecular Dynamics Simulation, Mutagenesis, Protein Structure, Tertiary, Serotonin Plasma Membrane Transport Proteins, Zinc",

author = "Per Plenge and Lei Shi and Thijs Beuming and Jerez Te and Newman, {Amy Hauck} and Harel Weinstein and Ulrik Gether and Loland, {Claus J}",

year = "2012",

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doi = "10.1074/jbc.M112.371765",

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T1 - Steric hindrance mutagenesis in the conserved extracellular vestibule impedes allosteric binding of antidepressants to the serotonin transporter

AU - Plenge, Per

AU - Shi, Lei

AU - Beuming, Thijs

AU - Te, Jerez

AU - Newman, Amy Hauck

AU - Weinstein, Harel

AU - Gether, Ulrik

AU - Loland, Claus J

PY - 2012/11/16

Y1 - 2012/11/16

N2 - Background: The serotonin transporter contains an allosteric binding site with unknown location. Results: We use molecular modeling, mutagenesis, and zinc site engineering to locate and inhibit the allosteric binding site. Conclusion: Data are consistent with the allosteric binding site being located in the extracellular vestibule. Significance: This opens the search for a new generation of antidepressant drugs directed toward the proposed allosteric binding site.

AB - Background: The serotonin transporter contains an allosteric binding site with unknown location. Results: We use molecular modeling, mutagenesis, and zinc site engineering to locate and inhibit the allosteric binding site. Conclusion: Data are consistent with the allosteric binding site being located in the extracellular vestibule. Significance: This opens the search for a new generation of antidepressant drugs directed toward the proposed allosteric binding site.

KW - Allosteric Site

KW - Antidepressive Agents, Second-Generation

KW - Citalopram

KW - Humans

KW - Molecular Docking Simulation

KW - Molecular Dynamics Simulation

KW - Mutagenesis

KW - Protein Structure, Tertiary

KW - Serotonin Plasma Membrane Transport Proteins

KW - Zinc

U2 - 10.1074/jbc.M112.371765

DO - 10.1074/jbc.M112.371765

M3 - Journal article

C2 - 23007398

SN - 0021-9258

VL - 287

SP - 39316

EP - 39326

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 47

ER -

Steric hindrance mutagenesis in the conserved extracellular vestibule impedes allosteric binding of antidepressants to the serotonin transporter

Abstract

Keywords

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