Revealing the location and dynamics of a concealed binding site in the dopamine transporter.

ABSTRACT: The dopamine transporter (DAT) is linked to neuropsychiatric disorders including ADHD, Parkinson's disease, and substance use disorders. Accordingly, DAT is the target of illicit drugs and clinically important medicines. However, the number and function of ligand binding sites in DAT is enigmatic due to conflicting data from available structures and molecular pharmacology. Herein, we design force sensors with DAT ligands and measure their interaction forces with wild-type and mutated DATs, from which two distinct populations of unbinding strengths and off-rates are detected. The high-force population is reduced by V152I and S422A mutations, or by substituting Na⁺ with K⁺ or NMDG⁺. In contrast, several modifications including mutation G386H, acetylation of K

SUBMITTER: Zhu R 

PROVIDER: S-EPMC12056086 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature