6O5R

Room temperature structure of binary complex of native hAChE with oxime reactivator RS-170B

6O5R の概要

• エントリーDOI: 10.2210/pdb6o5r/pdb
• 分子名称: Acetylcholinesterase, 4-carbamoyl-1-(3-{2-[(E)-(hydroxyimino)methyl]-1H-imidazol-1-yl}propyl)pyridin-1-ium, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: oxime reactivator, imidazole-based oxime, rs-170b, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 121195.46

構造登録者

Gerlits, O.,Kovalevsky, A.,Radic, Z. (登録日: 2019-03-04, 公開日: 2019-05-29, 最終更新日: 2024-11-20)

主引用文献

Gerlits, O.,Kong, X.,Cheng, X.,Wymore, T.,Blumenthal, D.K.,Taylor, P.,Radic, Z.,Kovalevsky, A.
Productive reorientation of a bound oxime reactivator revealed in room temperature X-ray structures of native and VX-inhibited human acetylcholinesterase.
J.Biol.Chem., 294:10607-10618, 2019

PubMed Abstract: Exposure to organophosphorus compounds (OPs) may be fatal if untreated, and a clear and present danger posed by nerve agent OPs has become palpable in recent years. OPs inactivate acetylcholinesterase (AChE) by covalently modifying its catalytic serine. Inhibited AChE cannot hydrolyze the neurotransmitter acetylcholine leading to its build-up at the cholinergic synapses and creating an acute cholinergic crisis. Current antidotes, including oxime reactivators that attack the OP-AChE conjugate to free the active enzyme, are inefficient. Better reactivators are sought, but their design is hampered by a conformationally rigid portrait of AChE extracted exclusively from 100K X-ray crystallography and scarcity of structural knowledge on human AChE (hAChE). Here, we present room temperature X-ray structures of native and VX-phosphonylated hAChE with an imidazole-based oxime reactivator, RS-170B. We discovered that inhibition with VX triggers substantial conformational changes in bound RS-170B from a "nonproductive" pose (the reactive aldoxime group points away from the VX-bound serine) in the reactivator-only complex to a "semi-productive" orientation in the VX-modified complex. This observation, supported by concurrent molecular simulations, suggested that the narrow active-site gorge of hAChE may be significantly more dynamic than previously thought, allowing RS-170B to reorient inside the gorge. Furthermore, we found that small molecules can bind in the choline-binding site hindering approach to the phosphorous of VX-bound serine. Our results provide structural and mechanistic perspectives on the reactivation of OP-inhibited hAChE and demonstrate that structural studies at physiologically relevant temperatures can deliver previously overlooked insights applicable for designing next-generation antidotes.

PubMed: 31138650
DOI: 10.1074/jbc.RA119.008725

実験手法

X-RAY DIFFRACTION (2.8 Å)