8v6u

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5HT2AR-miniGq heterotrimer in complex with a novel agonist obtained from large scale docking

Structural highlights

8v6u is a 5 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:Electron Microscopy, Resolution 3Å
Ligands:YEQ
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

5HT2A_HUMAN G-protein coupled receptor for 5-hydroxytryptamine (serotonin) (PubMed:1330647, PubMed:18703043, PubMed:19057895). Also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and lysergic acid diethylamide (LSD) (PubMed:28129538). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors (PubMed:28129538). Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways (PubMed:28129538). Signaling activates phospholipase C and a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and promotes the release of Ca(2+) ions from intracellular stores (PubMed:18703043, PubMed:28129538). Affects neural activity, perception, cognition and mood (PubMed:18297054). Plays a role in the regulation of behavior, including responses to anxiogenic situations and psychoactive substances. Plays a role in intestinal smooth muscle contraction, and may play a role in arterial vasoconstriction.[1] [2] [3] [4] [5] [6] [7] (Microbial infection) Acts as a receptor for human JC polyomavirus/JCPyV.[8]

Publication Abstract from PubMed

AlphaFold2 (AF2) models have had wide impact, but they have had mixed success in retrospective ligand recognition. We prospectively docked large libraries against unrefined AF2 models of the sigma2 and 5-HT2A receptors, testing hundreds of new molecules and comparing results to docking against the experimental structures. Hit rates were high and similar for the experimental and the AF2 structures, as were affinities. The success of docking against the AF2 models was achieved despite differences in orthosteric residue conformations versus the experimental structures. Determination of the cryo-electron microscopy structure for one of the more potent 5HT2A ligands from the AF2 docking revealed residue accommodations that resembled the AF2 prediction. AF2 models may sample conformations that differ from experimental structures but remain low energy and relevant for ligand discovery, extending the domain of structure-based ligand discovery.

AlphaFold2 structures guide prospective ligand discovery.,Lyu J, Kapolka N, Gumpper R, Alon A, Wang L, Jain MK, Barros-Alvarez X, Sakamoto K, Kim Y, DiBerto J, Kim K, Glenn IS, Tummino TA, Huang S, Irwin JJ, Tarkhanova OO, Moroz Y, Skiniotis G, Kruse AC, Shoichet BK, Roth BL Science. 2024 May 16:eadn6354. doi: 10.1126/science.adn6354. PMID:38753765[9]

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

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References

  1. ↑ Stam NJ, Van Huizen F, Van Alebeek C, Brands J, Dijkema R, Tonnaer JA, Olijve W. Genomic organization, coding sequence and functional expression of human 5-HT2 and 5-HT1A receptor genes. Eur J Pharmacol. 1992 Oct 1;227(2):153-62. PMID:1330647
  2. ↑ Gonzalez-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, Lopez-Gimenez JF, Zhou M, Okawa Y, Callado LF, Milligan G, Gingrich JA, Filizola M, Meana JJ, Sealfon SC. Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature. 2008 Mar 6;452(7183):93-7. doi: 10.1038/nature06612. Epub 2008 Feb 24. PMID:18297054 doi:http://dx.doi.org/10.1038/nature06612
  3. ↑ Cussac D, Boutet-Robinet E, Ailhaud MC, Newman-Tancredi A, Martel JC, Danty N, Rauly-Lestienne I. Agonist-directed trafficking of signalling at serotonin 5-HT2A, 5-HT2B and 5-HT2C-VSV receptors mediated Gq/11 activation and calcium mobilisation in CHO cells. Eur J Pharmacol. 2008 Oct 10;594(1-3):32-8. doi: 10.1016/j.ejphar.2008.07.040., Epub 2008 Jul 30. PMID:18703043 doi:http://dx.doi.org/10.1016/j.ejphar.2008.07.040
  4. ↑ Knauer CS, Campbell JE, Chio CL, Fitzgerald LW. Pharmacological characterization of mitogen-activated protein kinase activation by recombinant human 5-HT2C, 5-HT2A, and 5-HT2B receptors. Naunyn Schmiedebergs Arch Pharmacol. 2009 May;379(5):461-71. doi:, 10.1007/s00210-008-0378-4. Epub 2008 Dec 5. PMID:19057895 doi:http://dx.doi.org/10.1007/s00210-008-0378-4
  5. ↑ Albizu L, Holloway T, Gonzalez-Maeso J, Sealfon SC. Functional crosstalk and heteromerization of serotonin 5-HT2A and dopamine D2 receptors. Neuropharmacology. 2011 Sep;61(4):770-7. doi: 10.1016/j.neuropharm.2011.05.023., Epub 2011 May 27. PMID:21645528 doi:http://dx.doi.org/10.1016/j.neuropharm.2011.05.023
  6. ↑ Delille HK, Becker JM, Burkhardt S, Bleher B, Terstappen GC, Schmidt M, Meyer AH, Unger L, Marek GJ, Mezler M. Heterocomplex formation of 5-HT2A-mGlu2 and its relevance for cellular signaling cascades. Neuropharmacology. 2012 Jun;62(7):2184-91. doi: 10.1016/j.neuropharm.2012.01.010., Epub 2012 Jan 25. PMID:22300836 doi:http://dx.doi.org/10.1016/j.neuropharm.2012.01.010
  7. ↑ Wacker D, Wang S, McCorvy JD, Betz RM, Venkatakrishnan AJ, Levit A, Lansu K, Schools ZL, Che T, Nichols DE, Shoichet BK, Dror RO, Roth BL. Crystal Structure of an LSD-Bound Human Serotonin Receptor. Cell. 2017 Jan 26;168(3):377-389.e12. doi: 10.1016/j.cell.2016.12.033. PMID:28129538 doi:http://dx.doi.org/10.1016/j.cell.2016.12.033
  8. ↑ Assetta B, Maginnis MS, Gracia Ahufinger I, Haley SA, Gee GV, Nelson CD, O'Hara BA, Allen Ramdial SA, Atwood WJ. 5-HT2 receptors facilitate JC polyomavirus entry. J Virol. 2013 Dec;87(24):13490-8. doi: 10.1128/JVI.02252-13. Epub 2013 Oct 2. PMID:24089568 doi:http://dx.doi.org/10.1128/JVI.02252-13
  9. ↑ Lyu J, Kapolka N, Gumpper R, Alon A, Wang L, Jain MK, Barros-Álvarez X, Sakamoto K, Kim Y, DiBerto J, Kim K, Glenn IS, Tummino TA, Huang S, Irwin JJ, Tarkhanova OO, Moroz Y, Skiniotis G, Kruse AC, Shoichet BK, Roth BL. AlphaFold2 structures guide prospective ligand discovery. Science. 2024 May 16:eadn6354. PMID:38753765 doi:10.1126/science.adn6354

Contents


PDB ID 8v6u

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