Cryo-EM reveals two distinct serotonin-bound conformations of full-length 5-HT3A receptor

Sandip Basak, Yvonne Gicheru, Shanlin Rao, Mark S. P. Sansom and Sudha Chakrapani ()
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Sandip Basak: Case Western Reserve University
Yvonne Gicheru: Case Western Reserve University
Shanlin Rao: University of Oxford
Mark S. P. Sansom: University of Oxford
Sudha Chakrapani: Case Western Reserve University

Nature, 2018, vol. 563, issue 7730, 270-274

Abstract: Abstract The 5-HT3A serotonin receptor1, a cationic pentameric ligand-gated ion channel (pLGIC), is the clinical target for management of nausea and vomiting associated with radiation and chemotherapies2. Upon binding, serotonin induces a global conformational change that encompasses the ligand-binding extracellular domain (ECD), the transmembrane domain (TMD) and the intracellular domain (ICD), the molecular details of which are unclear. Here we present two serotonin-bound structures of the full-length 5-HT3A receptor in distinct conformations at 3.32 Å and 3.89 Å resolution that reveal the mechanism underlying channel activation. In comparison to the apo 5-HT3A receptor, serotonin-bound states underwent a large twisting motion in the ECD and TMD, leading to the opening of a 165 Å permeation pathway. Notably, this motion results in the creation of lateral portals for ion permeation at the interface of the TMD and ICD. Combined with molecular dynamics simulations, these structures provide novel insights into conformational coupling across domains and functional modulation.

Keywords: Lateral Portal; Conformational Coupling; Permeation Pathway; Pore Axis; Electrostatic Surface Potential Calculations (search for similar items in EconPapers)
Date: 2018
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Citations: View citations in EconPapers (5)

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DOI: 10.1038/s41586-018-0660-7

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