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

@article{citeulike:2923910, abstract = {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 [(3)H]CFT in the transporter, either by cross-linking engineered cysteines or with an engineered Zn(2+)-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.}, address = {Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York 10021, USA.}, author = {Beuming, Thijs and Kniazeff, Julie and Bergmann, Marianne L L. and Shi, Lei and Gracia, Luis and Raniszewska, Klaudia and Newman, Amy Hauck H. and Javitch, Jonathan A A. and Weinstein, Harel and Gether, Ulrik and Loland, Claus J J. }, citeulike-article-id = {2923910}, doi = {http://dx.doi.org/10.1038/nn.2146}, issn = {1097-6256}, journal = {Nature neuroscience}, month = {June}, posted-at = {2008-06-24 16:36:38}, priority = {2}, title = {The binding sites for cocaine and dopamine in the dopamine transporter overlap.}, url = {http://dx.doi.org/10.1038/nn.2146}, year = {2008} }

TY - JOUR ID - citeulike:2923910 L3 - citeulike-article-id:2923910 TI - The binding sites for cocaine and dopamine in the dopamine transporter overlap. JF - Nature neuroscience AD - Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York 10021, USA. SN - 1097-6256 N2 - 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 [(3)H]CFT in the transporter, either by cross-linking engineered cysteines or with an engineered Zn(2+)-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. AU - Beuming, Thijs AU - Kniazeff, Julie AU - Bergmann, Marianne L AU - Shi, Lei AU - Gracia, Luis AU - Raniszewska, Klaudia AU - Newman, Amy Hauck AU - Javitch, Jonathan A AU - Weinstein, Harel AU - Gether, Ulrik AU - Loland, Claus J PY - 2008/06/22/ UR - http://dx.doi.org/10.1038/nn.2146 ER -