Structure of the human dopamine transporter and mechanisms of inhibition.

ABSTRACT: The neurotransmitter dopamine has central roles in mood, appetite, arousal and movement¹. Despite its importance in brain physiology and function, and as a target for illicit and therapeutic drugs, the human dopamine transporter (hDAT) and mechanisms by which it is inhibited by small molecules and Zn²⁺ are without a high-resolution structural context. Here we determine the structure of hDAT in a tripartite complex with the competitive inhibitor and cocaine analogue, (-)-2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane² (β-CFT), the non-competitive inhibitor MRS7292³ and Zn²⁺ (ref. ⁴). We show how β-CFT occupies the central site, approximately halfway across the membrane, stabilizing the transporter in an outward-open

SUBMITTER: Srivastava DK 

PROVIDER: S-EPMC11324517 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature