7voe

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Crystal structure of 5-HT2AR in complex with aripiprazole

Structural highlights

7voe is a 1 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 2.9Å
Ligands:1PE, 9SC, CLR, MG, OLC
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

C562_ECOLX Electron-transport protein of unknown 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

Partial agonist activity at the dopamine D2 receptor (DRD2) is a key feature of third-generation antipsychotics (TGAs). However, TGAs also act as antagonists or weak partial agonists to the serotonin (5-hydroxytryptamine; 5-HT) 2A receptor (5-HT2AR). Here we present the crystal structures of aripiprazole- and cariprazine-bound human 5-HT2AR. Both TGAs adopt an unexpected 'upside-down' pose in the 5-HT2AR binding pocket, with secondary pharmacophores inserted in a similar way to a 'bolt'. This insight into the binding modes of TGAs offered a structural mechanism underlying their varied partial efficacies at 5-HT2AR and DRD2. These structures enabled the design of a partial agonist at DRD2/3 and 5-HT1AR with negligible 5-HT2AR binding that displayed potent antipsychotic-like activity without motor side effects in mice. This TGA lead also had antidepressant-like effects and improved cognitive performance in mouse models via 5-HT1AR. This work indicates that 5-HT2AR affinity is a dispensable contributor to the therapeutic actions of TGAs.

Structure-based design of a novel third-generation antipsychotic drug lead with potential antidepressant properties.,Chen Z, Fan L, Wang H, Yu J, Lu D, Qi J, Nie F, Luo Z, Liu Z, Cheng J, Wang S Nat Neurosci. 2021 Dec 9. pii: 10.1038/s41593-021-00971-w. doi:, 10.1038/s41593-021-00971-w. PMID:34887590[9]

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

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Citations
6 reviews cite this structure
"Selective" serotonin 5-HT<sub>2A</sub> receptor antagonists.
Casey et al. (2022)
5 more
10 other articles
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See Also

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. ↑ Chen Z, Fan L, Wang H, Yu J, Lu D, Qi J, Nie F, Luo Z, Liu Z, Cheng J, Wang S. Structure-based design of a novel third-generation antipsychotic drug lead with potential antidepressant properties. Nat Neurosci. 2021 Dec 9. pii: 10.1038/s41593-021-00971-w. doi:, 10.1038/s41593-021-00971-w. PMID:34887590 doi:http://dx.doi.org/10.1038/s41593-021-00971-w

Contents


PDB ID 7voe

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