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Title: Productive reorientation of a bound oxime reactivator revealed in room temperature X-ray structures of native and VX-inhibited human acetylcholinesterase

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). 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 bindmore » 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.« less

Authors:
 [1];  [2];  [2];  [3]; ORCiD logo [4]; ORCiD logo [5];  [5]; ORCiD logo [6]
+ Show Author Affiliations
  1. Univ. of Tennessee, Knoxville, TN (United States). Bredesen Center
  2. The Ohio State Univ., Columbus, OH (United States). Division of Medicinal Chemistry and Pharmacognosy. College of Pharmacy
  3. Univ. of Michigan, Ann Arbor, MI (United States). Dept. of Chemistry
  4. Univ. of Utah, Salt Lake City, UT (United States). Dept. of Pharmacology and Toxicology
  5. Univ. of California, San Diego, CA (United States). Skaggs School of Pharmacy and Pharmaceutical Sciences
  6. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Neutron Scattering Division
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Univ. of California, San Diego, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER); USDOE Office of Science (SC), Basic Energy Sciences (BES); National Inst. of Health (NIH) (United States)
OSTI Identifier:
1542204
Grant/Contract Number:  
AC05-00OR22725; AC02–06CH11357; U01 NS083451; R21 NS098998
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Biological Chemistry
Additional Journal Information:
Journal Volume: 294; Journal Issue: 27; Journal ID: ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular Biology
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; acetylcholinesterase (AChE); X-ray crystallography; molecular modeling; protein chemical modification; structure-function; oxime reactivator; reactivation mechanism; RS-170B; VX-inhibition

Citation Formats

Gerlits, Oksana, Kong, Xiaotian, Cheng, Xiaolin, Wymore, Troy, Blumenthal, Donald K., Taylor, Palmer, Radić, Zoran, and Kovalevsky, Andrey. Productive reorientation of a bound oxime reactivator revealed in room temperature X-ray structures of native and VX-inhibited human acetylcholinesterase. United States: N. p., 2019. Web. doi:10.1074/jbc.RA119.008725.
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Gerlits, Oksana, Kong, Xiaotian, Cheng, Xiaolin, Wymore, Troy, Blumenthal, Donald K., Taylor, Palmer, Radić, Zoran, & Kovalevsky, Andrey. Productive reorientation of a bound oxime reactivator revealed in room temperature X-ray structures of native and VX-inhibited human acetylcholinesterase. United States. https://doi.org/10.1074/jbc.RA119.008725
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Gerlits, Oksana, Kong, Xiaotian, Cheng, Xiaolin, Wymore, Troy, Blumenthal, Donald K., Taylor, Palmer, Radić, Zoran, and Kovalevsky, Andrey. Tue . "Productive reorientation of a bound oxime reactivator revealed in room temperature X-ray structures of native and VX-inhibited human acetylcholinesterase". United States. https://doi.org/10.1074/jbc.RA119.008725. https://www.osti.gov/servlets/purl/1542204.
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@article{osti_1542204,
title = {Productive reorientation of a bound oxime reactivator revealed in room temperature X-ray structures of native and VX-inhibited human acetylcholinesterase},
author = {Gerlits, Oksana and Kong, Xiaotian and Cheng, Xiaolin and Wymore, Troy and Blumenthal, Donald K. and Taylor, Palmer and Radić, Zoran and Kovalevsky, Andrey},
abstractNote = {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). 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.},
doi = {10.1074/jbc.RA119.008725},
journal = {Journal of Biological Chemistry},
number = 27,
volume = 294,
place = {United States},
year = {Tue May 28 00:00:00 EDT 2019},
month = {Tue May 28 00:00:00 EDT 2019}
}
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  • Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
  • Apollo - University of Cambridge Repository
  • DOI: 10.17863/cam.45787
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