6WV1

Crystal Structure of Recombinant Human Acetylcholinesterase In Complex with GB and HI-6

Summary for 6WV1

• Entry DOI: 10.2210/pdb6wv1/pdb
• Related: 6WUV 6WUY 6WUZ
• Descriptor: Acetylcholinesterase, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: nerve agent, acetylcholinesterase, tabun, ga, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 121640.90

Authors

McGuire, J.R.,Bester, S.M.,Pegan, S.D.,Height, J.J. (deposition date: 2020-05-05, release date: 2021-02-17, Last modification date: 2023-10-18)

Primary citation

McGuire, J.R.,Bester, S.M.,Guelta, M.A.,Cheung, J.,Langley, C.,Winemiller, M.D.,Bae, S.Y.,Funk, V.,Myslinski, J.M.,Pegan, S.D.,Height, J.J.
Structural and Biochemical Insights into the Inhibition of Human Acetylcholinesterase by G-Series Nerve Agents and Subsequent Reactivation by HI-6.
Chem.Res.Toxicol., 34:804-816, 2021

PubMed Abstract: The recent use of organophosphate nerve agents in Syria, Malaysia, Russia, and the United Kingdom has reinforced the potential threat of their intentional release. These agents act through their ability to inhibit human acetylcholinesterase (hAChE; E.C. 3.1.1.7), an enzyme vital for survival. The toxicity of hAChE inhibition via G-series nerve agents has been demonstrated to vary widely depending on the G-agent used. To gain insight into this issue, the structures of hAChE inhibited by tabun, sarin, cyclosarin, soman, and GP were obtained along with the inhibition kinetics for these agents. Through this information, the role of hAChE active site plasticity in agent selectivity is revealed. With reports indicating that the efficacy of reactivators can vary based on the nerve agent inhibiting hAChE, human recombinatorially expressed hAChE was utilized to define these variations for HI-6 among various G-agents. To identify the structural underpinnings of this phenomenon, the structures of tabun, sarin, and soman-inhibited hAChE in complex with HI-6 were determined. This revealed how the presence of G-agent adducts impacts reactivator access and placement within the active site. These insights will contribute toward a path of next-generation reactivators and an improved understanding of the innate issues with the current reactivators.

PubMed: 33538594
DOI: 10.1021/acs.chemrestox.0c00406

Experimental method

X-RAY DIFFRACTION (2.372 Å)