6W2B

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

6W2B の概要

• エントリーDOI: 10.2210/pdb6w2b/pdb
• 分子名称: Sodium-dependent serotonin transporter, 8B6 heavy chain antibody fragment, 8B6 light chain antibody fragment, ... (5 entities in total)
• 機能のキーワード: antidepressant, complex, transporter, antibody, transport protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 110887.10

構造登録者

Coleman, J.A.,Navratna, V.,Yang, D. (登録日: 2020-03-05, 公開日: 2020-03-25, 最終更新日: 2024-11-06)

主引用文献

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

実験手法

X-RAY DIFFRACTION (4.7 Å)