Cryo-EM structure of the dopamine transporter with a novel atypical non-competitive inhibitor bound to the orthosteric site

Clara Nautrup Pedersen; Fuyu Yang; Samantha Ita; Yibin Xu; Ravikumar Akunuri; Sofia Trampari; Caroline Marie Teresa Neumann; Lasse Messell Desdorf; Birgit Schiøtt; Joseph M Salvino; Ole Valente Mortensen; Poul Nissen; Azadeh Shahsavar

doi:10.1111/jnc.16179

Cryo-EM structure of the dopamine transporter with a novel atypical non-competitive inhibitor bound to the orthosteric site

Clara Nautrup Pedersen, Fuyu Yang, Samantha Ita, Yibin Xu, Ravikumar Akunuri, Sofia Trampari, Caroline Marie Teresa Neumann, Lasse Messell Desdorf, Birgit Schiøtt, Joseph M Salvino, Ole Valente Mortensen^*, Poul Nissen^*, Azadeh Shahsavar^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

1 Citationer (Scopus)

Abstract

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.)

Originalsprog	Engelsk
Tidsskrift	Journal of Neurochemistry
Vol/bind	168
Nummer	9
Sider (fra-til)	2043-2055
Antal sider	13
ISSN	0022-3042
DOI	https://doi.org/10.1111/jnc.16179
Status	Udgivet - sep. 2024

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Pedersen, C. N., Yang, F., Ita, S., Xu, Y., Akunuri, R., Trampari, S., Neumann, C. M. T., Desdorf, L. M., Schiøtt, B., Salvino, J. M., Mortensen, O. V., Nissen, P., & Shahsavar, A. (2024). Cryo-EM structure of the dopamine transporter with a novel atypical non-competitive inhibitor bound to the orthosteric site. Journal of Neurochemistry, 168(9), 2043-2055. https://doi.org/10.1111/jnc.16179

@article{e78a29fb784c437cbbefbd90d383d140,

title = "Cryo-EM structure of the dopamine transporter with a novel atypical non-competitive inhibitor bound to the orthosteric site",

abstract = "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 {\AA} 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.)",

keywords = "atypical inhibitor, cryo-electron microscopy, dopamine transporter, neurotransmitter transporter",

author = "Pedersen, {Clara Nautrup} and Fuyu Yang and Samantha Ita and Yibin Xu and Ravikumar Akunuri and Sofia Trampari and Neumann, {Caroline Marie Teresa} and Desdorf, {Lasse Messell} and Birgit Schi{\o}tt and Salvino, {Joseph M} and Mortensen, {Ole Valente} and Poul Nissen and Azadeh Shahsavar",

year = "2024",

month = sep,

doi = "10.1111/jnc.16179",

language = "English",

volume = "168",

pages = "2043--2055",

journal = "Journal of Neurochemistry",

issn = "0022-3042",

publisher = "John Wiley & Sons Inc.",

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Pedersen, CN, Yang, F, Ita, S, Xu, Y, Akunuri, R, Trampari, S, Neumann, CMT, Desdorf, LM , Schiøtt, B, Salvino, JM, Mortensen, OV, Nissen, P & Shahsavar, A 2024, 'Cryo-EM structure of the dopamine transporter with a novel atypical non-competitive inhibitor bound to the orthosteric site', Journal of Neurochemistry, bind 168, nr. 9, s. 2043-2055. https://doi.org/10.1111/jnc.16179

Cryo-EM structure of the dopamine transporter with a novel atypical non-competitive inhibitor bound to the orthosteric site. / Pedersen, Clara Nautrup; Yang, Fuyu; Ita, Samantha et al.
I: Journal of Neurochemistry, Bind 168, Nr. 9, 09.2024, s. 2043-2055.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

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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

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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.)

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KW - cryo-electron microscopy

KW - dopamine transporter

KW - neurotransmitter transporter

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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 -

Cryo-EM structure of the dopamine transporter with a novel atypical non-competitive inhibitor bound to the orthosteric site

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