TY - JOUR
T1 - Cryo-EM structure of the dopamine transporter with a novel atypical non-competitive inhibitor bound to the orthosteric site
AU - Pedersen, Clara Nautrup
AU - Yang, Fuyu
AU - Ita, Samantha
AU - Xu, Yibin
AU - Akunuri, Ravikumar
AU - Trampari, Sofia
AU - Neumann, Caroline Marie Teresa
AU - Desdorf, Lasse Messell
AU - Schiøtt, Birgit
AU - Salvino, Joseph M
AU - Mortensen, Ole Valente
AU - Nissen, Poul
AU - Shahsavar, Azadeh
PY - 2024/9
Y1 - 2024/9
N2 - The regulation of dopamine (DA) removal from the synaptic cleft is a crucial process in neurotransmission and is facilitated by the sodium- and chloride-coupled dopamine transporter DAT. Psychostimulant drugs, cocaine, and amphetamine, both block the uptake of DA, while amphetamine also triggers the release of DA. As a result, they prolong or even amplify neurotransmitter signaling. Atypical inhibitors of DAT lack cocaine-like rewarding effects and offer a promising strategy for the treatment of drug use disorders. Here, we present the 3.2 Å resolution cryo-electron microscopy structure of the Drosophila melanogaster dopamine transporter (dDAT) in complex with the atypical non-competitive inhibitor AC-4-248. The inhibitor partially binds at the central binding site, extending into the extracellular vestibule, and locks the transporter in an outward open conformation. Our findings propose mechanisms for the non-competitive inhibition of DAT and attenuation of cocaine potency by AC-4-248 and provide a basis for the rational design of more efficacious atypical inhibitors. (Figure presented.)
AB - The regulation of dopamine (DA) removal from the synaptic cleft is a crucial process in neurotransmission and is facilitated by the sodium- and chloride-coupled dopamine transporter DAT. Psychostimulant drugs, cocaine, and amphetamine, both block the uptake of DA, while amphetamine also triggers the release of DA. As a result, they prolong or even amplify neurotransmitter signaling. Atypical inhibitors of DAT lack cocaine-like rewarding effects and offer a promising strategy for the treatment of drug use disorders. Here, we present the 3.2 Å resolution cryo-electron microscopy structure of the Drosophila melanogaster dopamine transporter (dDAT) in complex with the atypical non-competitive inhibitor AC-4-248. The inhibitor partially binds at the central binding site, extending into the extracellular vestibule, and locks the transporter in an outward open conformation. Our findings propose mechanisms for the non-competitive inhibition of DAT and attenuation of cocaine potency by AC-4-248 and provide a basis for the rational design of more efficacious atypical inhibitors. (Figure presented.)
KW - atypical inhibitor
KW - cryo-electron microscopy
KW - dopamine transporter
KW - neurotransmitter transporter
UR - http://www.scopus.com/inward/record.url?scp=85198645555&partnerID=8YFLogxK
U2 - 10.1111/jnc.16179
DO - 10.1111/jnc.16179
M3 - Journal article
C2 - 39010681
SN - 0022-3042
VL - 168
SP - 2043
EP - 2055
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 9
ER -