7um4

Crystal structure of inactive 5-HT5AR in complex with AS2674723Crystal structure of inactive 5-HT5AR in complex with AS2674723

Structural highlights

7um4 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.8Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

5HT5A_HUMAN G-protein coupled receptor for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone and a mitogen (PubMed:35610220, PubMed:35835867, PubMed:9865521). Also functions as a receptor for ergot alkaloid derivatives and other psychoactive substances (PubMed:35835867). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors (PubMed:35610220, PubMed:35835867, PubMed:9865521). HTR5A is coupled to G(i)/G(o) G alpha proteins and mediates inhibitory neurotransmission: signaling inhibits adenylate cyclase activity and activates a phosphatidylinositol-calcium second messenger system that regulates the release of Ca(2+) ions from intracellular stores (PubMed:35610220, PubMed:35835867, PubMed:9865521).^[1] ^[2] ^[3]

Publication Abstract from PubMed

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)(5A) receptor (5-HT(5A)R) is the least understood and lacks selective tool compounds. Here, we report four high-resolution (2.73-2.80 A) structures of human 5-HT(5A)Rs, 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-HT(5A)R. Collectively, these findings both enhance our understanding of this enigmatic receptor and provide a roadmap for structure-based drug discovery for 5-HT(5A)R.

Inactive and active state structures template selective tools for the human 5-HT(5A) receptor.,Zhang S, Chen H, Zhang C, Yang Y, Popov P, Liu J, Krumm BE, Cao C, Kim K, Xiong Y, Katritch V, Shoichet BK, Jin J, Fay JF, Roth BL Nat Struct Mol Biol. 2022 Jul;29(7):677-687. doi: 10.1038/s41594-022-00796-6. , Epub 2022 Jul 14. PMID:35835867^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Tan Y, Xu P, Huang S, Yang G, Zhou F, He X, Ma H, Xu HE, Jiang Y. Structural insights into the ligand binding and G(i) coupling of serotonin receptor 5-HT(5A). Cell Discov. 2022 May 24;8(1):50. PMID:35610220 doi:10.1038/s41421-022-00412-3
↑ Zhang S, Chen H, Zhang C, Yang Y, Popov P, Liu J, Krumm BE, Cao C, Kim K, Xiong Y, Katritch V, Shoichet BK, Jin J, Fay JF, Roth BL. Inactive and active state structures template selective tools for the human 5-HT5A receptor. Nat Struct Mol Biol. 2022 Jul;29(7):677-687. doi: 10.1038/s41594-022-00796-6., Epub 2022 Jul 14. PMID:35835867 doi:http://dx.doi.org/10.1038/s41594-022-00796-6
↑ Francken BJ, Jurzak M, Vanhauwe JF, Luyten WH, Leysen JE. The human 5-ht5A receptor couples to Gi/Go proteins and inhibits adenylate cyclase in HEK 293 cells. Eur J Pharmacol. 1998 Nov 20;361(2-3):299-309. PMID:9865521 doi:10.1016/s0014-2999(98)00744-4
↑ Zhang S, Chen H, Zhang C, Yang Y, Popov P, Liu J, Krumm BE, Cao C, Kim K, Xiong Y, Katritch V, Shoichet BK, Jin J, Fay JF, Roth BL. Inactive and active state structures template selective tools for the human 5-HT5A receptor. Nat Struct Mol Biol. 2022 Jul;29(7):677-687. doi: 10.1038/s41594-022-00796-6., Epub 2022 Jul 14. PMID:35835867 doi:http://dx.doi.org/10.1038/s41594-022-00796-6

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OCA

[1] Tan Y, Xu P, Huang S, Yang G, Zhou F, He X, Ma H, Xu HE, Jiang Y. Structural insights into the ligand binding and G(i) coupling of serotonin receptor 5-HT(5A). Cell Discov. 2022 May 24;8(1):50. PMID:35610220 doi:10.1038/s41421-022-00412-3

[2] Zhang S, Chen H, Zhang C, Yang Y, Popov P, Liu J, Krumm BE, Cao C, Kim K, Xiong Y, Katritch V, Shoichet BK, Jin J, Fay JF, Roth BL. Inactive and active state structures template selective tools for the human 5-HT5A receptor. Nat Struct Mol Biol. 2022 Jul;29(7):677-687. doi: 10.1038/s41594-022-00796-6., Epub 2022 Jul 14. PMID:35835867 doi:http://dx.doi.org/10.1038/s41594-022-00796-6

[3] Francken BJ, Jurzak M, Vanhauwe JF, Luyten WH, Leysen JE. The human 5-ht5A receptor couples to Gi/Go proteins and inhibits adenylate cyclase in HEK 293 cells. Eur J Pharmacol. 1998 Nov 20;361(2-3):299-309. PMID:9865521 doi:10.1016/s0014-2999(98)00744-4

[4] Zhang S, Chen H, Zhang C, Yang Y, Popov P, Liu J, Krumm BE, Cao C, Kim K, Xiong Y, Katritch V, Shoichet BK, Jin J, Fay JF, Roth BL. Inactive and active state structures template selective tools for the human 5-HT5A receptor. Nat Struct Mol Biol. 2022 Jul;29(7):677-687. doi: 10.1038/s41594-022-00796-6., Epub 2022 Jul 14. PMID:35835867 doi:http://dx.doi.org/10.1038/s41594-022-00796-6

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