Jonathan A. Coleman, Dongxue Yang, Zhiyu Zhao, Po-Chao Wen, Craig Yoshioka,
Emad Tajkhorshid, and Eric Gouaux.
Serotonin transporter-ibogaine complexes illuminate mechanisms of
inhibition and transport.
Nature, 569:141-145, 2019.
(PMC: PMC6750207)
COLE2019-ET
The serotonin transporter (SERT) regulates neurotransmitter homeostasis
through the sodium-
and chloride-dependent recycling of serotonin into presynaptic neurons1-3.
Major depression
and anxiety disorders are treated using selective serotonin reuptake
inhibitors (SSRIs), small
molecules that competitively block substrate binding, prolonging
neurotransmitter action2,4.
The dopamine and norepinephrine transporters, together with SERT, are
members of the
neurotransmitter sodium symporter (NSS) family. Cocaine and
amphetamines inhibit or
modulate the transport activities of NSSs2,3 and genetic variants are
associated with multiple
neuropsychiatric disorders including attention deficit hyperactivity disorder,
autism, and bipolar
disorder2,5. Studies of bacterial NSS homologs, including LeuT, have shown
how
transmembrane helices (TMs) undergo conformational changes during the
transport cycle,
exposing a central binding site to either side of the membrane1,6-12.
However, the
conformational changes associated with transport in eukaryotic NSSs remain
obscure. To
elucidate structure-based mechanisms for transport in SERT, we turned to
complexes with
ibogaine, a centuries old hallucinogenic natural product with psychoactive
and anti-addictive
properties13,14 (Fig. 1a). Interestingly, ibogaine displays non-competitive
inhibition of transport,
yet it exhibits competitive binding toward SSRIs15,16. Here we report cryo-
EM structures of
SERT-ibogaine complexes captured in outward-open, occluded, and inward-
open
conformations. Ibogaine binds to the central binding site and closure of the
extracellular gate
largely involves movements of TMs 1b and 6a. Opening of the intracellular
gate involves a hinge-
like movement of TM1a and partial unwinding of TM5, which together create
a permeation
pathway enabling substrate and ion diffusion to the cytoplasm. These
structures define the
structural rearrangements that occur from outward-open to the inward-open
conformations,
providing insight into the mechanism of neurotransmitter transport and
ibogaine inhibition.
Download Full Text
The manuscripts available on our site are provided for your personal
use only and may not be retransmitted or redistributed without written
permissions from the paper's publisher and author. You may not upload any
of this site's material to any public server, on-line service, network, or
bulletin board without prior written permission from the publisher and
author. You may not make copies for any commercial purpose. Reproduction
or storage of materials retrieved from this web site is subject to the
U.S. Copyright Act of 1976, Title 17 U.S.C.
