7lwd

From Proteopedia

Cryo-EM structure of the wild-type human serotonin transporter complexed with vilazodone, imipramine and 15B8 Fab

Structural highlights

7lwd is a 3 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.65Å
Ligands:	IXX, NAG, YG7
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SC6A4_HUMAN Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into the pre-synaptic terminal for re-utilization. Plays a key role in mediating regulation of the availability of serotonin to other receptors of serotonergic systems. Terminates the action of serotonin and recycles it in a sodium-dependent manner.^[1] ^[2] ^[3]

Publication Abstract from PubMed

Depression is a common mental disorder. The standard medical treatment is the selective serotonin reuptake inhibitors (SSRIs). All characterized SSRIs are competitive inhibitors of the serotonin transporter (SERT). A non-competitive inhibitor may produce a more favorable therapeutic profile. Vilazodone is an antidepressant with limited information on its molecular interactions with SERT. Here we use molecular pharmacology and cryo-EM structural elucidation to characterize vilazodone binding to SERT. We find that it exhibits non-competitive inhibition of serotonin uptake and impedes dissociation of [(3)H]imipramine at low nanomolar concentrations. Our SERT structure with bound imipramine and vilazodone reveals a unique binding pocket for vilazodone, expanding the boundaries of the extracellular vestibule. Characterization of the binding site is substantiated with molecular dynamics simulations and systematic mutagenesis of interacting residues resulting in decreased vilazodone binding to the allosteric site. Our findings underline the versatility of SERT allosteric ligands and describe the unique binding characteristics of vilazodone.

The antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter.,Plenge P, Yang D, Salomon K, Laursen L, Kalenderoglou IE, Newman AH, Gouaux E, Coleman JA, Loland CJ Nat Commun. 2021 Aug 20;12(1):5063. doi: 10.1038/s41467-021-25363-3. PMID:34417466^[4]

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

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Citations

6 reviews cite this structure

Membranes under the Magnetic Lens: A Dive into the Diverse World of Membrane Protein Structures Using Cryo-EM.

Piper et al. (2022)

5 more

21 other articles

No citations found

References

↑ Brenner B, Harney JT, Ahmed BA, Jeffus BC, Unal R, Mehta JL, Kilic F. Plasma serotonin levels and the platelet serotonin transporter. J Neurochem. 2007 Jul;102(1):206-15. Epub 2007 May 15. PMID:17506858 doi:http://dx.doi.org/10.1111/j.1471-4159.2007.04542.x
↑ Ahmed BA, Jeffus BC, Bukhari SI, Harney JT, Unal R, Lupashin VV, van der Sluijs P, Kilic F. Serotonin transamidates Rab4 and facilitates its binding to the C terminus of serotonin transporter. J Biol Chem. 2008 Apr 4;283(14):9388-98. doi: 10.1074/jbc.M706367200. Epub 2008, Jan 28. PMID:18227069 doi:http://dx.doi.org/10.1074/jbc.M706367200
↑ Ahmed BA, Bukhari IA, Jeffus BC, Harney JT, Thyparambil S, Ziu E, Fraer M, Rusch NJ, Zimniak P, Lupashin V, Tang D, Kilic F. The cellular distribution of serotonin transporter is impeded on serotonin-altered vimentin network. PLoS One. 2009;4(3):e4730. doi: 10.1371/journal.pone.0004730. Epub 2009 Mar 9. PMID:19270731 doi:http://dx.doi.org/10.1371/journal.pone.0004730
↑ Plenge P, Yang D, Salomon K, Laursen L, Kalenderoglou IE, Newman AH, Gouaux E, Coleman JA, Loland CJ. The antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter. Nat Commun. 2021 Aug 20;12(1):5063. PMID:34417466 doi:10.1038/s41467-021-25363-3

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

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PDB ID 7lwd

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7lwd

From Proteopedia

Cryo-EM structure of the wild-type human serotonin transporter complexed with vilazodone, imipramine and 15B8 Fab

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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