6DS0

Structural Determinants of Activation and Biased Agonism at the 5-HT2B Receptor

Summary for 6DS0

• Entry DOI: 10.2210/pdb6ds0/pdb
• Descriptor: 5HT2B receptor, BRIL chimera, CHOLESTEROL, (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate, ... (6 entities in total)
• Functional Keywords: gpcr, 5ht2b, setotonin receptor, lisuride, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 47270.07

Authors

McCorvy, J.D.,Wacker, D.,Wang, S.,Agegnehu, B.,Liu, J.,Lansu, K.,Tribo, A.R.,Olsen, R.H.J.,Che, T.,Jin, J.,Roth, B.L. (deposition date: 2018-06-13, release date: 2018-08-29, Last modification date: 2024-10-30)

Primary citation

McCorvy, J.D.,Wacker, D.,Wang, S.,Agegnehu, B.,Liu, J.,Lansu, K.,Tribo, A.R.,Olsen, R.H.J.,Che, T.,Jin, J.,Roth, B.L.
Structural determinants of 5-HT2Breceptor activation and biased agonism.
Nat. Struct. Mol. Biol., 25:787-796, 2018

PubMed Abstract: Serotonin (5-hydroxytryptamine; 5-HT) receptors modulate a variety of physiological processes ranging from perception, cognition and emotion to vascular and smooth muscle contraction, platelet aggregation, gastrointestinal function and reproduction. Drugs that interact with 5-HT receptors effectively treat diseases as diverse as migraine headaches, depression and obesity. Here we present four structures of a prototypical serotonin receptor-the human 5-HT receptor-in complex with chemically and pharmacologically diverse drugs, including methysergide, methylergonovine, lisuride and LY266097. A detailed analysis of these structures complemented by comprehensive interrogation of signaling illuminated key structural determinants essential for activation. Additional structure-guided mutagenesis experiments revealed binding pocket residues that were essential for agonist-mediated biased signaling and β-arrestin2 translocation. Given the importance of 5-HT receptors for a large number of therapeutic indications, insights derived from these studies should accelerate the design of safer and more effective medications.

PubMed: 30127358
DOI: 10.1038/s41594-018-0116-7

Experimental method

X-RAY DIFFRACTION (3.188 Å)