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

Gerlits, Oksana; Kong, Xiaotian; Cheng, Xiaolin; Wymore, Troy; Blumenthal, Donald K.; Taylor, Palmer; Radić, Zoran; Kovalevsky, Andrey

doi:10.1074/jbc.RA119.008725

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

Journal Article · Tue May 28 00:00:00 EDT 2019 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.RA119.008725· OSTI ID:1542204

Gerlits, Oksana ^[1]; Kong, Xiaotian ^[2]; Cheng, Xiaolin ^[2]; Wymore, Troy ^[3];

^[4];

^[5]; Radić, Zoran ^[5];

^[6]

Univ. of Tennessee, Knoxville, TN (United States). Bredesen Center
The Ohio State Univ., Columbus, OH (United States). Division of Medicinal Chemistry and Pharmacognosy. College of Pharmacy
Univ. of Michigan, Ann Arbor, MI (United States). Dept. of Chemistry
Univ. of Utah, Salt Lake City, UT (United States). Dept. of Pharmacology and Toxicology
Univ. of California, San Diego, CA (United States). Skaggs School of Pharmacy and Pharmaceutical Sciences
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Neutron Scattering Division

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.

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Research Organization:: Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Univ. of California, San Diego, CA (United States)

Sponsoring Organization:: 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)

Grant/Contract Number:: AC05-00OR22725; AC02–06CH11357; U01 NS083451; R21 NS098998

OSTI ID:: 1542204

Journal Information:: Journal of Biological Chemistry, Vol. 294, Issue 27; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 10 works

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Rational design, synthesis, and evaluation of uncharged, “smart” bis-oxime antidotes of organophosphate-inhibited human acetylcholinesterase

Journal Article · Tue Feb 04 00:00:00 EST 2020 · Journal of Biological Chemistry · OSTI ID:1542204

Gorecki, Lukas; Gerlits, Oksana; Kong, Xiaotian; +6 more

Quaternary and tertiary aldoxime antidotes for organophosphate exposure in a zebrafish model system

Journal Article · Wed Apr 15 00:00:00 EDT 2015 · Toxicology and Applied Pharmacology · OSTI ID:1542204

Schmidt, Hayden R.; Radić, Zoran; Taylor, Palmer

Related Subjects

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

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

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