Gerlits_2019_J.Biol.Chem_294_10607

Reference

Title : Productive reorientation of a bound oxime reactivator revealed in room temperature X-ray structures of native and VX-inhibited human acetylcholinesterase - Gerlits_2019_J.Biol.Chem_294_10607
Author(s) : Gerlits O , Kong X , Cheng X , Wymore T , Blumenthal DK , Taylor P , Radic Z , Kovalevsky A
Ref : Journal of Biological Chemistry , 294 :10607 , 2019
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.

PubMedSearch : Gerlits_2019_J.Biol.Chem_294_10607
PubMedID: 31138650
Gene_locus related to this paper: human-ACHE

Related information

Inhibitor VX
Gene_locus VX    human-ACHE
Structure VX    human-ACHE    6O66    6O5R    6O5S    6O5V
Reactivator VX    human-ACHE    6O66    6O5R    6O5S    6O5V    RS170B

Citations formats

Gerlits O, Kong X, Cheng X, Wymore T, Blumenthal DK, Taylor P, Radic Z, Kovalevsky A (2019)
Productive reorientation of a bound oxime reactivator revealed in room temperature X-ray structures of native and VX-inhibited human acetylcholinesterase
Journal of Biological Chemistry 294 :10607

Gerlits O, Kong X, Cheng X, Wymore T, Blumenthal DK, Taylor P, Radic Z, Kovalevsky A (2019)
Journal of Biological Chemistry 294 :10607