7AMD

In situ assembly of choline acetyltransferase ligands by a hydrothiolation reaction reveals key determinants for inhibitor design

7AMD の概要

• エントリーDOI: 10.2210/pdb7amd/pdb
• 分子名称: Choline O-acetyltransferase, [[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-4-oxidanyl-3-phosphonooxy-oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(3~{R})-2,2-dimethyl-4-[[3-[2-[(1~{R})-2-(1-methylpyridin-4-yl)-1-naphthalen-1-yl-ethyl]sulfanylethylamino]-3-oxidanylidene-propyl]amino]-3-oxidanyl-4-oxidanylidene-butyl] hydrogen phosphate, SODIUM ION, ... (4 entities in total)
• 機能のキーワード: chat, inhibitor, avp, hydrothiolation, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 69173.19

構造登録者

Allgardsson, A.,Ekstrom, F.J.,Wiktelius, D.,Bergstrom, T.,Hoster, N.,Akfur, C.,Forsgren, N.,Lejon, C.,Hedenstrom, M.,Linusson, A. (登録日: 2020-10-08, 公開日: 2020-10-28, 最終更新日: 2024-01-31)

主引用文献

Wiktelius, D.,Allgardsson, A.,Bergstrom, T.,Hoster, N.,Akfur, C.,Forsgren, N.,Lejon, C.,Hedenstrom, M.,Linusson, A.,Ekstrom, F.
In Situ Assembly of Choline Acetyltransferase Ligands by a Hydrothiolation Reaction Reveals Key Determinants for Inhibitor Design.
Angew.Chem.Int.Ed.Engl., 60:813-819, 2021

PubMed Abstract: The potential drug target choline acetyltransferase (ChAT) catalyses the production of the neurotransmitter acetylcholine in cholinergic neurons, T-cells, and B-cells. Herein, we show that arylvinylpyridiniums (AVPs), the most widely studied class of ChAT inhibitors, act as substrate in an unusual coenzyme A-dependent hydrothiolation reaction. This in situ synthesis yields an adduct that is the actual enzyme inhibitor. The adduct is deeply buried in the active site tunnel of ChAT and interactions with a hydrophobic pocket near the choline binding site have major implications for the molecular recognition of inhibitors. Our findings clarify the inhibition mechanism of AVPs, establish a drug modality that exploits a target-catalysed reaction between exogenous and endogenous precursors, and provide new directions for the development of ChAT inhibitors with improved potency and bioactivity.

PubMed: 33079431
DOI: 10.1002/anie.202011989

実験手法

X-RAY DIFFRACTION (2.25 Å)