Abstract
Na+/Cl--coupled biogenic amine transporters are the primary targets of therapeutic and abused drugs, ranging from antidepressants to the psychostimulants cocaine and amphetamines, and to their cognate substrates. Here we determine X-ray crystal structures of the Drosophila melanogaster dopamine transporter (dDAT) bound to its substrate dopamine, a substrate analogue 3,4-dichlorophenethylamine, the psychostimulants d-amphetamine and methamphetamine, or to cocaine and cocaine analogues. All ligands bind to the central binding site, located approximately halfway across the membrane bilayer, in close proximity to bound sodium and chloride ions. The central binding site recognizes three chemically distinct classes of ligands via conformational changes that accommodate varying sizes and shapes, thus illustrating molecular principles that distinguish substrates from inhibitors in biogenic amine transporters.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 322-327 |
| Number of pages | 6 |
| Journal | Nature |
| Volume | 521 |
| Issue number | 7552 |
| DOIs | |
| State | Published - May 21 2015 |
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Neurotransmitter and psychostimulant recognition by the dopamine transporter. / Wang, Kevin H.; Penmatsa, Aravind; Gouaux, Eric.
In: Nature, Vol. 521, No. 7552, 21.05.2015, p. 322-327.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Neurotransmitter and psychostimulant recognition by the dopamine transporter
AU - Wang, Kevin H.
AU - Penmatsa, Aravind
AU - Gouaux, Eric
PY - 2015/5/21
Y1 - 2015/5/21
N2 - Na+/Cl--coupled biogenic amine transporters are the primary targets of therapeutic and abused drugs, ranging from antidepressants to the psychostimulants cocaine and amphetamines, and to their cognate substrates. Here we determine X-ray crystal structures of the Drosophila melanogaster dopamine transporter (dDAT) bound to its substrate dopamine, a substrate analogue 3,4-dichlorophenethylamine, the psychostimulants d-amphetamine and methamphetamine, or to cocaine and cocaine analogues. All ligands bind to the central binding site, located approximately halfway across the membrane bilayer, in close proximity to bound sodium and chloride ions. The central binding site recognizes three chemically distinct classes of ligands via conformational changes that accommodate varying sizes and shapes, thus illustrating molecular principles that distinguish substrates from inhibitors in biogenic amine transporters.
AB - Na+/Cl--coupled biogenic amine transporters are the primary targets of therapeutic and abused drugs, ranging from antidepressants to the psychostimulants cocaine and amphetamines, and to their cognate substrates. Here we determine X-ray crystal structures of the Drosophila melanogaster dopamine transporter (dDAT) bound to its substrate dopamine, a substrate analogue 3,4-dichlorophenethylamine, the psychostimulants d-amphetamine and methamphetamine, or to cocaine and cocaine analogues. All ligands bind to the central binding site, located approximately halfway across the membrane bilayer, in close proximity to bound sodium and chloride ions. The central binding site recognizes three chemically distinct classes of ligands via conformational changes that accommodate varying sizes and shapes, thus illustrating molecular principles that distinguish substrates from inhibitors in biogenic amine transporters.
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U2 - 10.1038/nature14431
DO - 10.1038/nature14431
M3 - Article
C2 - 25970245
AN - SCOPUS:84930204469
VL - 521
SP - 322
EP - 327
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7552
ER -