In a recent study published in the journal Nature , researchers presented the molecular structure of dopamine transporter (DAT) complexed with cocaine. Cocaine is highly addictive, and its misuse can exacerbate psychiatric disorders. Although it exerts effects by binding to monoamine transporters, its inhibition of DAT underlies its addictive and rewarding properties.
Currently, there are no experimental human DAT (hDAT) structures. Nevertheless, insights from homologs, such as solute carrier 6 (SLC6) family members and Drosophila melanogaster DAT (dDAT), have provided structural information. Study: Structure of the human dopamine transporter in complex with cocaine .
Image Credit: Naeblys / Shutterstock These reveal a common architecture of 12 transmembrane helices (TM1–TM12) in a pseudo-symmetric fold (the LeuT fold), with the substrate-binding site in the core. In all SLC6 family members, the central substrate-binding site can be accessed from the intracellular or extracellular membrane face, with energy for substrate transport derived from sodium ion (Na + ) co-transport. While many also depend on chloride ions (Cl - ), whether Cl - is bound/transported remains unclear.
Cl - binding in DAT may allosterically reduce the affinity of the second sodium site (Na2). The Na2 site may be necessary for transporter isomerization to an inward-facing state before substrate release, which then transitions to an outward-open conformation. In the dDAT-cocaine complex, cocaine binds .