5AIN

Varenicline Interactions at the 5HT3 Receptor Ligand Binding Site are Revealed by 5HTBP

5AIN の概要

• エントリーDOI: 10.2210/pdb5ain/pdb
• 分子名称: SOLUBLE ACETYLCHOLINE RECEPTOR, VARENICLINE (3 entities in total)
• 機能のキーワード: serotonin binding protein
• 由来する生物種: APLYSIA CALIFORNICA (CALIFORNIA SEA HARE)
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 121550.88

構造登録者

Price, K.L.,Lillestol, R.,Ulens, C.,Lummis, S.C. (登録日: 2015-02-16, 公開日: 2015-03-25, 最終更新日: 2024-11-06)

主引用文献

Price, K.L.,Lillestol, R.K.,Ulens, C.,Lummis, S.C.R.
Varenicline Interactions at the 5-Ht3 Receptor Ligand Binding Site are Revealed by 5-Htbp.
Acs Chem Neurosci, 6:1151-, 2015

PubMed Abstract: Cys-loop receptors are the site of action of many therapeutic drugs. One of these is the smoking cessation agent varenicline, which has its major therapeutic effects at nicotinic acetylcholine (nACh) receptors but also acts at 5-HT3 receptors. Here, we report the X-ray crystal structure of the 5-HT binding protein (5-HTBP) in complex with varenicline, and test the predicted interactions by probing the potency of varenicline in a range of mutant 5-HT3 receptors expressed in HEK293 cells and Xenopus oocytes. The structure reveals a range of interactions between varenicline and 5-HTBP. We identified residues within 5 Å of varenicline and substituted the equivalent residues in the 5-HT3 receptor with Ala or a residue with similar chemical properties. Functional characterization of these mutant 5-HT3 receptors, using a fluorescent membrane potential dye in HEK cells and voltage clamp in oocytes, supports interactions between varenicline and the receptor that are similar to those in 5-HTBP. The structure also revealed C-loop closure that was less than in the 5-HT-bound 5-HTBP, and hydrogen bonding between varenicline and the complementary face of the binding pocket via a water molecule, which are characteristics consistent with partial agonist behavior of varenicline in the 5-HT3 receptor. Together, these data reveal detailed insights into the molecular interaction of varenicline in the 5-HT3 receptor.

PubMed: 25648658
DOI: 10.1021/CN500369H

実験手法

X-RAY DIFFRACTION (2.3 Å)