6DG8

Full-length 5-HT3A receptor in a serotonin-bound conformation- State 2

Summary for 6DG8

• Entry DOI: 10.2210/pdb6dg8/pdb
• EMDB information: 7882 7883
• Descriptor: 5-hydroxytryptamine receptor 3A, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: membrane protein
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 5
• Total formula weight: 270676.10

Authors

Basak, S.,Chakrapani, S. (deposition date: 2018-05-17, release date: 2018-11-07, Last modification date: 2024-11-13)

Primary citation

Basak, S.,Gicheru, Y.,Rao, S.,Sansom, M.S.P.,Chakrapani, S.
Cryo-EM reveals two distinct serotonin-bound conformations of full-length 5-HT3Areceptor.
Nature, 563:270-274, 2018

PubMed 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 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.

PubMed: 30401837
DOI: 10.1038/s41586-018-0660-7

Experimental method

ELECTRON MICROSCOPY (3.89 Å)