Abstract
Acetylcholinesterase (AChE) is a critical enzyme that regulates neurotransmission by degrading the neurotransmitter acetylcholine in synapses of the nervous system. It is an important target for both therapeutic drugs that treat Alzheimer’s disease and organophosphate (OP) chemical warfare agents that cripple the nervous system and cause death through paralysis. We are exploring a strategy to design compounds that bind tightly at or near a peripheral or P-site near the mouth of the AChE active site gorge and exclude OPs from the active site while interfering minimally with the passage of acetylcholine. However, to target the AChE P-site, much more information must be gathered about the structure-activity relationships of ligands that bind specifically to the P-site. Here, we review our recent reports on two uncharged, natural product inhibitors of AChE, dihydrotanshinone I and territrem B, that have relatively high affinities for the enzyme. We describe an inhibitor competition assay and comment on the structures of these inhibitors in complex with recombinant human acetylcholinesterase as determined by X-ray crystallography. Our results reveal that dihydrotanshinone I binding is specific to only the P-site, while territrem B binding spans the P-site and extends into the acylation or A-site at the base of the gorge.
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Abbreviations
- AChE:
-
Acetylcholinesterase
- OPs:
-
Organophosphates
- RMSD:
-
Root-mean-square deviation
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This work was supported by contract HDTRA1-11-C-0017 from the Department of Defense and the New York Structural Biology Center.
Throughout this paper, we number amino acid residues according to the human AChE sequence (Uniprot accession number P22303).
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Cheung, J., Beri, V., Shiomi, K. et al. Acetylcholinesterase Complexes with the Natural Product Inhibitors Dihydrotanshinone I and Territrem B: Binding Site Assignment from Inhibitor Competition and Validation Through Crystal Structure Determination. J Mol Neurosci 53, 506–510 (2014). https://doi.org/10.1007/s12031-014-0261-3
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DOI: https://doi.org/10.1007/s12031-014-0261-3