Monoamine transporters: structure, intrinsic dynamics and allosteric regulation

Abstract

Monoamine transporters (MATs) regulate neurotransmission via the reuptake of dopamine, serotonin and norepinephrine from extra-neuronal regions and thus maintain neurotransmitter homeostasis. As targets of a wide range of compounds, including antidepressants, substances of abuse and drugs for neuropsychiatric and neurodegenerative disorders, their mechanism of action and their modulation by small molecules have long been of broad interest. Recent advances in the structural characterization of dopamine and serotonin transporters have opened the way for structure-based modeling and simulations, which, together with experimental data, now provide mechanistic understanding of their transport function and interactions. Here we review recent progress in the elucidation of the structural dynamics of MATs and their conformational landscape and transitions, as well as allosteric regulation mechanisms.

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Fig. 1: Architecture of MATs, represented by the structures of human serotonin transporter (hSERT) and D. melanogaster dopamine transporter (dDAT).
Fig. 2: The primary site S1 for substrate binding serves as an orthosteric drug-binding site in hSERT and dDAT.
Fig. 3: Neurotransmitter transport cycle of hDAT.
Fig. 4: Conformational space and structural dynamics of hDAT, and signature dynamics of MATs.
Fig. 5: Effect of small molecules bound to orthosteric (S1) sites and allosteric (S2) sites on intrinsic dynamics.

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Acknowledgements

Supported by the US National Institutes of Health awards P41GM103712 and P30DA035778 (I.B.). The authors thank S. Zhang for generating Fig. 4d.

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Correspondence to Ivet Bahar.

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Peer review information: Katarzyna Marcinkiewicz was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Cheng, M.H., Bahar, I. Monoamine transporters: structure, intrinsic dynamics and allosteric regulation. Nat Struct Mol Biol 26, 545–556 (2019). https://doi.org/10.1038/s41594-019-0253-7

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