6W2B

Anomalous bromine signal reveals the position of Br-paroxetine complexed with the serotonin transporter at the central site

Summary for 6W2B

• Entry DOI: 10.2210/pdb6w2b/pdb
• Descriptor: Sodium-dependent serotonin transporter, 8B6 heavy chain antibody fragment, 8B6 light chain antibody fragment, ... (5 entities in total)
• Functional Keywords: antidepressant, complex, transporter, antibody, transport protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 110887.10

Authors

Coleman, J.A.,Navratna, V.,Yang, D. (deposition date: 2020-03-05, release date: 2020-03-25, Last modification date: 2024-11-06)

Primary citation

Coleman, J.A.,Navratna, V.,Antermite, D.,Yang, D.,Bull, J.A.,Gouaux, E.
Chemical and structural investigation of the paroxetine-human serotonin transporter complex.
Elife, 9:-, 2020

PubMed Abstract: Antidepressants target the serotonin transporter (SERT) by inhibiting serotonin reuptake. Structural and biochemical studies aiming to understand binding of small-molecules to conformationally dynamic transporters like SERT often require thermostabilizing mutations and antibodies to stabilize a specific conformation, leading to questions about relationships of these structures to the bonafide conformation and inhibitor binding poses of wild-type transporter. To address these concerns, we determined the structures of ∆N72/∆C13 and ts2-inactive SERT bound to paroxetine analogues using single-particle cryo-EM and x-ray crystallography, respectively. We synthesized enantiopure analogues of paroxetine containing either bromine or iodine instead of fluorine. We exploited the anomalous scattering of bromine and iodine to define the pose of these inhibitors and investigated inhibitor binding to Asn177 mutants of ts2-active SERT. These studies provide mutually consistent insights into how paroxetine and its analogues bind to the central substrate-binding site of SERT, stabilize the outward-open conformation, and inhibit serotonin transport.

PubMed: 32618269
DOI: 10.7554/eLife.56427

Experimental method

X-RAY DIFFRACTION (4.7 Å)