The binding sites for cocaine and dopamine in the dopamine transporter overlap

被引：267

作者：

Beuming, Thijs ^{[2
]}

Kniazeff, Julie ^{[1
]}

Bergmann, Marianne L. ^{[1
]}

Shi, Lei ^{[2
,3
]}

Gracia, Luis ^{[2
]}

Raniszewska, Klaudia ^{[1
]}

Newman, Amy Hauck ^{[4
]}

Javitch, Jonathan A. ^{[5
,6
,7
]}

Weinstein, Harel ^{[2
,3
]}

Gether, Ulrik ^{[1
]}

Loland, Claus J. ^{[1
]}

机构：

[1] Univ Copenhagen, Panum Inst 18 6, Fac Hlth Sci, Dept Neurosci & Pharmacol,Mol Neuropharmacol Grp, DK-2200 Copenhagen, Denmark

[2] Cornell Univ, Weill Med Coll, Dept Physiol & Biophys, New York, NY 10021 USA

[3] Cornell Univ, Weill Med Coll, Inst Computat Biomed, New York, NY 10021 USA

[4] Natl Inst Drug Abuse, Med Chem Sect, Medicat Discovery Res Branch,NIH, Intramural Res Program,Dept Hlth & Human Servs, Baltimore, MD 21224 USA

[5] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY 10023 USA

[6] Columbia Univ, Coll Phys & Surg, Dept Pharmacol, New York, NY 10023 USA

[7] Columbia Univ, Coll Phys & Surg, Ctr Mol Recognit, New York, NY 10023 USA

来源：

NATURE NEUROSCIENCE | 2008年 / 11卷 / 07期

关键词：

D O I：

10.1038/nn.2146

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Cocaine is a widely abused substance with psychostimulant effects that are attributed to inhibition of the dopamine transporter (DAT). We present molecular models for DAT binding of cocaine and cocaine analogs constructed from the high-resolution structure of the bacterial transporter homolog LeuT. Our models suggest that the binding site for cocaine and cocaine analogs is deeply buried between transmembrane segments 1, 3, 6 and 8, and overlaps with the binding sites for the substrates dopamine and amphetamine, as well as for benztropine-like DAT inhibitors. We validated our models by detailed mutagenesis and by trapping the radiolabeled cocaine analog [H-3] CFT in the transporter, either by cross-linking engineered cysteines or with an engineered Zn2+-binding site that was situated extracellularly to the predicted common binding pocket. Our data demonstrate the molecular basis for the competitive inhibition of dopamine transport by cocaine.

引用

页码：780 / 789

页数：10

共 47 条

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