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Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters

Author

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  • Atsuko Yamashita

    (Department of Biochemistry and Molecular Biophysics)

  • Satinder K. Singh

    (Department of Biochemistry and Molecular Biophysics)

  • Toshimitsu Kawate

    (Department of Biochemistry and Molecular Biophysics)

  • Yan Jin

    (Columbia University)

  • Eric Gouaux

    (Department of Biochemistry and Molecular Biophysics
    Columbia University)

Abstract

Na+/Cl--dependent transporters terminate synaptic transmission by using electrochemical gradients to drive the uptake of neurotransmitters, including the biogenic amines, from the synapse to the cytoplasm of neurons and glia. These transporters are the targets of therapeutic and illicit compounds, and their dysfunction has been implicated in multiple diseases of the nervous system. Here we present the crystal structure of a bacterial homologue of these transporters from Aquifex aeolicus, in complex with its substrate, leucine, and two sodium ions. The protein core consists of the first ten of twelve transmembrane segments, with segments 1–5 related to 6–10 by a pseudo-two-fold axis in the membrane plane. Leucine and the sodium ions are bound within the protein core, halfway across the membrane bilayer, in an occluded site devoid of water. The leucine and ion binding sites are defined by partially unwound transmembrane helices, with main-chain atoms and helix dipoles having key roles in substrate and ion binding. The structure reveals the architecture of this important class of transporter, illuminates the determinants of substrate binding and ion selectivity, and defines the external and internal gates.

Suggested Citation

  • Atsuko Yamashita & Satinder K. Singh & Toshimitsu Kawate & Yan Jin & Eric Gouaux, 2005. "Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters," Nature, Nature, vol. 437(7056), pages 215-223, September.
    • Handle: RePEc:nat:nature:v:437:y:2005:i:7056:d:10.1038_nature03978
    DOI: 10.1038/nature03978
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    Cited by:

    1. Gabriel Núñez-Vivanco & Angélica Fierro & Pablo Moya & Patricio Iturriaga-Vásquez & Miguel Reyes-Parada, 2018. "3D similarities between the binding sites of monoaminergic target proteins," PLOS ONE, Public Library of Science, vol. 13(7), pages 1-18, July.
    2. Hyun Deok Song & Fangqiang Zhu, 2015. "Conformational Changes in Two Inter-Helical Loops of Mhp1 Membrane Transporter," PLOS ONE, Public Library of Science, vol. 10(7), pages 1-19, July.
    3. Solveig G. Schmidt & Mette Galsgaard Malle & Anne Kathrine Nielsen & Søren S.-R. Bohr & Ciara F. Pugh & Jeppe C. Nielsen & Ida H. Poulsen & Kasper D. Rand & Nikos S. Hatzakis & Claus J. Loland, 2022. "The dopamine transporter antiports potassium to increase the uptake of dopamine," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. David B. Sauer & Jennifer J. Marden & Joseph C. Sudar & Jinmei Song & Christopher Mulligan & Da-Neng Wang, 2022. "Structural basis of ion – substrate coupling in the Na+-dependent dicarboxylate transporter VcINDY," Nature Communications, Nature, vol. 13(1), pages 1-9, December.

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