6NP0

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

Summary for 6NP0

• Entry DOI: 10.2210/pdb6np0/pdb
• EMDB information: 0469
• Descriptor: 5-hydroxytryptamine receptor 3A, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: membrane protein
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 5
• Total formula weight: 290284.84

Authors

Basak, S.,Chakrapani, S. (deposition date: 2019-01-17, release date: 2019-07-24, Last modification date: 2020-07-29)

Primary citation

Basak, S.,Gicheru, Y.,Kapoor, A.,Mayer, M.L.,Filizola, M.,Chakrapani, S.
Molecular mechanism of setron-mediated inhibition of full-length 5-HT3Areceptor.
Nat Commun, 10:3225-3225, 2019

PubMed Abstract: Serotonin receptor (5-HTR) is the most common therapeutic target to manage the nausea and vomiting during cancer therapies and in the treatment of irritable bowel syndrome. Setrons, a class of competitive antagonists, cause functional inhibition of 5-HTR in the gastrointestinal tract and brainstem, acting as effective anti-emetic agents. Despite their prevalent use, the molecular mechanisms underlying setron binding and inhibition of 5-HTR are not fully understood. Here, we present the structure of granisetron-bound full-length 5-HTR solved by single-particle cryo-electron microscopy to 2.92 Å resolution. The reconstruction reveals the orientation of granisetron in the orthosteric site with unambiguous density for interacting sidechains. Molecular dynamics simulations and electrophysiology confirm the granisetron binding orientation and the residues central for ligand recognition. Comparison of granisetron-bound 5-HTR with the apo and serotonin-bound structures, reveals key insights into the mechanism underlying 5-HTR inhibition.

PubMed: 31324772
DOI: 10.1038/s41467-019-11142-8

Experimental method

ELECTRON MICROSCOPY (2.92 Å)