TCB Publications - Abstract

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.

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.

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