8bla | pdb_00008bla

Human serotonin 5-HT3A receptor in complex with vortioxetine (detergent, ECD only, active/distorted conformation)

Structural highlights

8bla 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 3.3Å
Ligands:	NAG, VTX
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

5HT3A_HUMAN Forms serotonin (5-hydroxytryptamine/5-HT3)-activated cation-selective channel complexes, which when activated cause fast, depolarizing responses in neurons.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Vortioxetine (VTX) is a recently approved antidepressant that targets a variety of serotonin receptors. Here, we investigate the drug's molecular mechanism of operation at the serotonin 5-HT(3) receptor (5-HT(3)R), which features two properties: VTX acts differently on rodent and human 5-HT(3)R, and VTX appears to suppress any subsequent response to agonists. Using a combination of cryo-EM, electrophysiology, voltage-clamp fluorometry and molecular dynamics, we show that VTX stabilizes a resting inhibited state of the mouse 5-HT(3)R and an agonist-bound-like state of human 5-HT(3)R, in line with the functional profile of the drug. We report four human 5-HT(3)R structures and show that the human receptor transmembrane domain is intrinsically fragile. We also explain the lack of recovery after VTX administration via a membrane partition mechanism.

Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT(3) receptors.,Lopez-Sanchez U, Munro LJ, Ladefoged LK, Pedersen AJ, Brun CC, Lyngby SM, Baud D, Juillan-Binard C, Pedersen MG, Lummis SCR, Bang-Andersen B, Schiott B, Chipot C, Schoehn G, Neyton J, Dehez F, Nury H, Kristensen AS Nat Struct Mol Biol. 2024 May 2. doi: 10.1038/s41594-024-01282-x. PMID:38698207^[5]

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

References

↑ Dubin AE, Huvar R, D'Andrea MR, Pyati J, Zhu JY, Joy KC, Wilson SJ, Galindo JE, Glass CA, Luo L, Jackson MR, Lovenberg TW, Erlander MG. The pharmacological and functional characteristics of the serotonin 5-HT(3A) receptor are specifically modified by a 5-HT(3B) receptor subunit. J Biol Chem. 1999 Oct 22;274(43):30799-810. PMID:10521471 doi:10.1074/jbc.274.43.30799
↑ Kelley SP, Dunlop JI, Kirkness EF, Lambert JJ, Peters JA. A cytoplasmic region determines single-channel conductance in 5-HT3 receptors. Nature. 2003 Jul 17;424(6946):321-4. PMID:12867984 doi:10.1038/nature01788
↑ Niesler B, Walstab J, Combrink S, Möller D, Kapeller J, Rietdorf J, Bönisch H, Göthert M, Rappold G, Brüss M. Characterization of the novel human serotonin receptor subunits 5-HT3C,5-HT3D, and 5-HT3E. Mol Pharmacol. 2007 Jul;72(1):8-17. PMID:17392525 doi:10.1124/mol.106.032144
↑ Davies PA, Pistis M, Hanna MC, Peters JA, Lambert JJ, Hales TG, Kirkness EF. The 5-HT3B subunit is a major determinant of serotonin-receptor function. Nature. 1999 Jan 28;397(6717):359-63. PMID:9950429 doi:10.1038/16941
↑ López-Sánchez U, Munro LJ, Ladefoged LK, Pedersen AJ, Brun CC, Lyngby SM, Baud D, Juillan-Binard C, Pedersen MG, Lummis SCR, Bang-Andersen B, Schiøtt B, Chipot C, Schoehn G, Neyton J, Dehez F, Nury H, Kristensen AS. Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT(3) receptors. Nat Struct Mol Biol. 2024 May 2. PMID:38698207 doi:10.1038/s41594-024-01282-x

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Dubin AE, Huvar R, D'Andrea MR, Pyati J, Zhu JY, Joy KC, Wilson SJ, Galindo JE, Glass CA, Luo L, Jackson MR, Lovenberg TW, Erlander MG. The pharmacological and functional characteristics of the serotonin 5-HT(3A) receptor are specifically modified by a 5-HT(3B) receptor subunit. J Biol Chem. 1999 Oct 22;274(43):30799-810. PMID:10521471 doi:10.1074/jbc.274.43.30799

[2] Kelley SP, Dunlop JI, Kirkness EF, Lambert JJ, Peters JA. A cytoplasmic region determines single-channel conductance in 5-HT3 receptors. Nature. 2003 Jul 17;424(6946):321-4. PMID:12867984 doi:10.1038/nature01788

[3] Niesler B, Walstab J, Combrink S, Möller D, Kapeller J, Rietdorf J, Bönisch H, Göthert M, Rappold G, Brüss M. Characterization of the novel human serotonin receptor subunits 5-HT3C,5-HT3D, and 5-HT3E. Mol Pharmacol. 2007 Jul;72(1):8-17. PMID:17392525 doi:10.1124/mol.106.032144

[4] Davies PA, Pistis M, Hanna MC, Peters JA, Lambert JJ, Hales TG, Kirkness EF. The 5-HT3B subunit is a major determinant of serotonin-receptor function. Nature. 1999 Jan 28;397(6717):359-63. PMID:9950429 doi:10.1038/16941

[5] López-Sánchez U, Munro LJ, Ladefoged LK, Pedersen AJ, Brun CC, Lyngby SM, Baud D, Juillan-Binard C, Pedersen MG, Lummis SCR, Bang-Andersen B, Schiøtt B, Chipot C, Schoehn G, Neyton J, Dehez F, Nury H, Kristensen AS. Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT(3) receptors. Nat Struct Mol Biol. 2024 May 2. PMID:38698207 doi:10.1038/s41594-024-01282-x

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[5]

8bla | pdb_00008bla

Human serotonin 5-HT3A receptor in complex with vortioxetine (detergent, ECD only, active/distorted conformation)

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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