7UM4

Crystal structure of inactive 5-HT5AR in complex with AS2674723

Summary for 7UM4

• Entry DOI: 10.2210/pdb7um4/pdb
• Descriptor: 5-hydroxytryptamine receptor 5A, PGS, TRIETHYLENE GLYCOL, ... (8 entities in total)
• Functional Keywords: gpcr, inactive state, membrane protein, 5-ht5ar, htr5a
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 61523.41

Authors

Zhang, S.,Roth, B.L. (deposition date: 2022-04-06, release date: 2022-07-20, Last modification date: 2024-10-23)

Primary citation

Zhang, S.,Chen, H.,Zhang, C.,Yang, Y.,Popov, P.,Liu, J.,Krumm, B.E.,Cao, C.,Kim, K.,Xiong, Y.,Katritch, V.,Shoichet, B.K.,Jin, J.,Fay, J.F.,Roth, B.L.
Inactive and active state structures template selective tools for the human 5-HT 5A receptor.
Nat.Struct.Mol.Biol., 29:677-687, 2022

PubMed Abstract: Serotonin receptors are important targets for established therapeutics and drug development as they are expressed throughout the human body and play key roles in cell signaling. There are 12 serotonergic G protein-coupled receptor members encoded in the human genome, of which the 5-hydroxytryptamine (5-HT) receptor (5-HTR) is the least understood and lacks selective tool compounds. Here, we report four high-resolution (2.73-2.80 Å) structures of human 5-HTRs, including an inactive state structure bound to an antagonist AS2674723 by crystallization and active state structures bound to a partial agonist lisuride and two full agonists, 5-carboxamidotryptamine (5-CT) and methylergometrine, by cryo-EM. Leveraging the new structures, we developed a highly selective and potent antagonist for 5-HTR. Collectively, these findings both enhance our understanding of this enigmatic receptor and provide a roadmap for structure-based drug discovery for 5-HTR.

PubMed: 35835867
DOI: 10.1038/s41594-022-00796-6

Experimental method

X-RAY DIFFRACTION (2.8 Å)