National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
1R01GM108921
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
3R01GM108921-03S1
United States
American Heart Association
17POST33671152
United States
Citation
Journal: Nature / Year: 2018 Title: Cryo-EM reveals two distinct serotonin-bound conformations of full-length 5-HT receptor. Authors: Sandip Basak / Yvonne Gicheru / Shanlin Rao / Mark S P Sansom / Sudha Chakrapani / Abstract: The 5-HT serotonin receptor, a cationic pentameric ligand-gated ion channel (pLGIC), is the clinical target for management of nausea and vomiting associated with radiation and chemotherapies. Upon ...The 5-HT serotonin receptor, a cationic pentameric ligand-gated ion channel (pLGIC), is the clinical target for management of nausea and vomiting associated with radiation and chemotherapies. 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-HT 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-HT 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.
History
Deposition
May 17, 2018
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Header (metadata) release
May 30, 2018
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Map release
Nov 7, 2018
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Update
Nov 20, 2024
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Current status
Nov 20, 2024
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Model: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 15 sec.
Vitrification
Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK I / Details: blot for 2.5 seconds.
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Electron microscopy
Microscope
FEI TITAN KRIOS
Image recording
Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Frames/image: 2-39 / Number real images: 2810 / Average electron dose: 40.0 e/Å2
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
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