6W1J

Cryo-EM structure of 5HT3A receptor in presence of Alosetron

Summary for 6W1J

• Entry DOI: 10.2210/pdb6w1j/pdb
• EMDB information: 21511 21512 21518
• Descriptor: 5-hydroxytryptamine receptor 3A, 2-acetamido-2-deoxy-beta-D-glucopyranose-(4-4)-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, ... (6 entities in total)
• Functional Keywords: transport protein
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 5
• Total formula weight: 268894.53

Authors

Basak, S.,Chakrapani, S. (deposition date: 2020-03-04, release date: 2021-01-13, Last modification date: 2024-10-23)

Primary citation

Basak, S.,Kumar, A.,Ramsey, S.,Gibbs, E.,Kapoor, A.,Filizola, M.,Chakrapani, S.
High-resolution structures of multiple 5-HT 3A R-setron complexes reveal a novel mechanism of competitive inhibition.
Elife, 9:-, 2020

PubMed Abstract: Serotonin receptors (5-HTR) play a crucial role in regulating gut movement, and are the principal target of setrons, a class of high-affinity competitive antagonists, used in the management of nausea and vomiting associated with radiation and chemotherapies. Structural insights into setron-binding poses and their inhibitory mechanisms are just beginning to emerge. Here, we present high-resolution cryo-EM structures of full-length 5-HTR in complex with palonosetron, ondansetron, and alosetron. Molecular dynamic simulations of these structures embedded in a fully-hydrated lipid environment assessed the stability of ligand-binding poses and drug-target interactions over time. Together with simulation results of apo- and serotonin-bound 5-HTR, the study reveals a distinct interaction fingerprint between the various setrons and binding-pocket residues that may underlie their diverse affinities. In addition, varying degrees of conformational change in the setron-5-HTR structures, throughout the channel and particularly along the channel activation pathway, suggests a novel mechanism of competitive inhibition.

PubMed: 33063666
DOI: 10.7554/eLife.57870

Experimental method

ELECTRON MICROSCOPY (2.92 Å)