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Title | Dopamine reuptake and inhibitory mechanisms in human dopamine transporter. |
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Journal, issue, pages | Nature, Vol. 632, Issue 8025, Page 686-694, Year 2024 |
Publish date | Aug 7, 2024 |
![]() | Yue Li / Xianping Wang / Yufei Meng / Tuo Hu / Jun Zhao / Renjie Li / Qinru Bai / Pu Yuan / Jun Han / Kun Hao / Yiqing Wei / Yunlong Qiu / Na Li / Yan Zhao / ![]() |
PubMed Abstract | The dopamine transporter has a crucial role in regulation of dopaminergic neurotransmission by uptake of dopamine into neurons and contributes to the abuse potential of psychomotor stimulants. ...The dopamine transporter has a crucial role in regulation of dopaminergic neurotransmission by uptake of dopamine into neurons and contributes to the abuse potential of psychomotor stimulants. Despite decades of study, the structure, substrate binding, conformational transitions and drug-binding poses of human dopamine transporter remain unknown. Here we report structures of the human dopamine transporter in its apo state, and in complex with the substrate dopamine, the attention deficit hyperactivity disorder drug methylphenidate, and the dopamine-uptake inhibitors GBR12909 and benztropine. The dopamine-bound structure in the occluded state precisely illustrates the binding position of dopamine and associated ions. The structures bound to drugs are captured in outward-facing or inward-facing states, illuminating distinct binding modes and conformational transitions during substrate transport. Unlike the outward-facing state, which is stabilized by cocaine, GBR12909 and benztropine stabilize the dopamine transporter in the inward-facing state, revealing previously unseen drug-binding poses and providing insights into how they counteract the effects of cocaine. This study establishes a framework for understanding the functioning of the human dopamine transporter and developing therapeutic interventions for dopamine transporter-related disorders and cocaine addiction. |
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Methods | EM (single particle) |
Resolution | 2.8 - 3.16 Å |
Structure data | EMDB-38850, PDB-8y2c: EMDB-38851, PDB-8y2d: EMDB-38852, PDB-8y2e: EMDB-38853: structure of a proteinACryo-EM structure of human dopamine transporter in complex with GBR12909 EMDB-38854, PDB-8y2g: |
Chemicals | ![]() ChemComp-NAG: ![]() ChemComp-LDP: ![]() ChemComp-NA: ![]() ChemComp-CL: ![]() ChemComp-HOH: ![]() ChemComp-CXQ: ![]() PDB-1d5s: ![]() PDB-1d5u: |
Source |
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![]() | MEMBRANE PROTEIN / human dopamine transporter in apo state / human dopamine transporter in complex with dopamine / human dopamine transporter in complex with benztropine / human dopamine transporter human dopamine transporter / human dopamine transporter in complex with methylphenidate |