Chloride binding site of neurotransmitter sodium symporters

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  • Adriana Krassimirova Kantcheva
  • ,
  • Matthias Quick, Center for Molecular Recognition and Departments of Psychiatry and Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY 10032; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY 10032, USA
  • Lei Shi, Department of Physiology and Biophysics, Weill Cornell Medical College, Cornell University, New York, NY 10065; His Royal Highness Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, Cornell University, New York, NY 10021, USA
  • Anne-Marie Lund Winther, Danmark
  • Sebastian Stolzenberg, Department of Physiology and Biophysics, Weill Cornell Medical College, Cornell University, New York, NY 10065; Department of Physics, Cornell University, Ithaca, NY 14853 , USA
  • Harel Weinstein, Department of Physiology and Biophysics, Weill Cornell Medical College, Cornell University, New York, NY 10065; His Royal Highness Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, Cornell University, New York, NY 10021, USA
  • Jonathan A. Javitch, Center for Molecular Recognition and Departments of Psychiatry and Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA
  • Poul Nissen
Neurotransmitter:sodium symporters (NSSs) play a critical role in signaling by reuptake of neurotransmitters. Eukaryotic NSSs are chloride-dependent, whereas prokaryotic NSS homologs like LeuT are chloride-independent but contain an acidic residue (Glu290 in LeuT) at a site where eukaryotic NSSs have a serine. The LeuT-E290S mutant displays chloride-dependent activity. We show that, in LeuT-E290S cocrystallized with bromide or chloride, the anion is coordinated by side chain hydroxyls from Tyr47, Ser290, and Thr254 and the side chain amide of Gln250. The bound anion and the nearby sodium ion in the Na1 site organize a connection between their coordinating residues and the extracellular gate of LeuT through a continuous H-bond network. The specific insights from the structures, combined with results from substrate binding studies and molecular dynamics simulations, reveal an anion-dependent occlusion mechanism for NSS and shed light on the functional role of chloride binding
OriginalsprogEngelsk
TidsskriftProceedings of the National Academy of Sciences of the United States of America
Vol/bind110
Nummer21
Sider (fra-til)8489-8494
Antal sider6
ISSN0027-8424
DOI
StatusUdgivet - 21 maj 2013

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