TY - JOUR
T1 - Structural basis for recognition of diverse antidepressants by the human serotonin transporter
AU - Coleman, Jonathan A.
AU - Gouaux, Eric
N1 - Funding Information:
We thank L. Vaskalis for assistance with figures, H. Owen for help with manuscript preparation, and members of the laboratory of E.G. for discussion. We acknowledge the staff of the Berkeley Center for Structural Biology at the Advanced Light Source and the Northeastern Collaborative Access Team at the Advanced Photon Source for assistance with data collection. J.A.C. is supported by a Banting postdoctoral fellowship from the Canadian Institutes of Health Research. We are particularly grateful to B. LaCroute and J. LaCroute for their generous support, as well as for funding from the National Institutes of Health (NIH) (5R37MH070039) to E.G. E.G. is supported as an Investigator of the Howard Hughes Medical Institute.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/2/1
Y1 - 2018/2/1
N2 - Selective serotonin reuptake inhibitors are clinically prescribed antidepressants that act by increasing the local concentrations of neurotransmitters at synapses and in extracellular spaces via blockade of the serotonin transporter. Here we report X-ray structures of engineered thermostable variants of the human serotonin transporter bound to the antidepressants sertraline, fluvoxamine, and paroxetine. The drugs prevent serotonin binding by occupying the central substrate-binding site and stabilizing the transporter in an outward-open conformation. These structures explain how residues within the central site orchestrate binding of chemically diverse inhibitors and mediate transporter drug selectivity.
AB - Selective serotonin reuptake inhibitors are clinically prescribed antidepressants that act by increasing the local concentrations of neurotransmitters at synapses and in extracellular spaces via blockade of the serotonin transporter. Here we report X-ray structures of engineered thermostable variants of the human serotonin transporter bound to the antidepressants sertraline, fluvoxamine, and paroxetine. The drugs prevent serotonin binding by occupying the central substrate-binding site and stabilizing the transporter in an outward-open conformation. These structures explain how residues within the central site orchestrate binding of chemically diverse inhibitors and mediate transporter drug selectivity.
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U2 - 10.1038/s41594-018-0026-8
DO - 10.1038/s41594-018-0026-8
M3 - Article
C2 - 29379174
AN - SCOPUS:85042770790
SN - 1545-9993
VL - 25
SP - 170
EP - 175
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
IS - 2
ER -