9HCO

Outward-open structure of human serotonin transporter bound to vilazodone

Summary for 9HCO

• Entry DOI: 10.2210/pdb9hco/pdb
• EMDB information: 52050
• Descriptor: Sodium-dependent serotonin transporter, 15B8 Fab heavy chain, 15B8 Fab light chain, ... (7 entities in total)
• Functional Keywords: monoamine transporter, leut fold, antidepressant binding, inhibitor complex, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 124714.90

Authors

Kalenderoglou, I.E.,Tillmann, P.,Loland, C.J. (deposition date: 2024-11-11, release date: 2025-09-17, Last modification date: 2026-05-20)

Primary citation

Kalenderoglou, I.E.,Nygaard, A.,Vogt, C.D.,Turaev, A.,Pape, T.,Adams, N.B.P.,Newman, A.H.,Loland, C.J.
Structural basis of vilazodone dual binding mode to the serotonin transporter.
Nat Commun, 16:10119-10119, 2025

PubMed Abstract: The serotonin transporter (SERT) plays a pivotal role in regulating serotonin (5-HT) signaling and is a key target in the treatment of psychiatric disorders. SERT has a binding site (S1) for 5-HT that also serves as a high-affinity binding site for antidepressants. The antidepressant vilazodone has been shown to inhibit SERT by binding to an allosteric site. Here, we present the cryo-EM structure of SERT with vilazodone bound to the S1 site and extending towards the allosteric site. We systematically dissect the vilazodone molecule into fragments and find that the terminal indole ring is the key determinant of its high affinity to SERT. Further, unlike typical Na-dependent SERT-selective antidepressants, vilazodone exhibits a dissociation constant (K) for purified SERT in the nanomolar range both in the presence and absence of Na. We substantiate this binding mode by exploring the conformational impact of vilazodone binding to SERT using site-specific insertion of the fluorescent non-canonical amino acid Anap. Our results offer molecular insight into the distinct pharmacological profile of a clinically used polymodal antidepressant.

PubMed: 41253806
DOI: 10.1038/s41467-025-65202-3

Experimental method

ELECTRON MICROSCOPY (2.78 Å)