8dt5

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X-ray structure of human acetylcholinesterase ternary complex with paraoxon and oxime RS170B (POX-hAChE-RS170B)

Structural highlights

8dt5 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.6Å
Ligands:DEP, GOL, LND
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ACES_HUMAN Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Role in neuronal apoptosis.[1] [2] [3] [4]

Publication Abstract from PubMed

Organophosphorus (OP) compounds, including nerve agents and some pesticides, covalently bind to the catalytic serine of human acetylcholinesterase (hAChE), thereby inhibiting acetylcholine hydrolysis necessary for efficient neurotransmission. Oxime antidotes can reactivate the OP-conjugated hAChE, but reactivation efficiency can be low for pesticides, such as paraoxon (POX). Understanding structural and dynamic determinants of OP inhibition and reactivation can provide insights to design improved reactivators. Here, X-ray structures of hAChE with unaged POX, with POX and oximes MMB4 and RS170B, and with MMB4 are reported. A significant conformational distortion of the acyl loop was observed upon POX binding, being partially restored to the native conformation by oximes. Neutron vibrational spectroscopy combined with molecular dynamics simulations showed that picosecond vibrational dynamics of the acyl loop soften in the approximately 20-50 cm(-1) frequency range. The acyl loop structural perturbations may be correlated with its picosecond vibrational dynamics to yield more comprehensive template for structure-based reactivator design.

Structural and dynamic effects of paraoxon binding to human acetylcholinesterase by X-ray crystallography and inelastic neutron scattering.,Gerlits O, Fajer M, Cheng X, Blumenthal DK, Radic Z, Kovalevsky A Structure. 2022 Oct 12. pii: S0969-2126(22)00373-2. doi:, 10.1016/j.str.2022.09.006. PMID:36265484[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
1 reviews cite this structure
Connectivity between surface and interior in catalytic subunits of acetylcholinesterases inferred from their X-ray structures.
Radić et al. (2024)
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4 other articles
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References

  1. ↑ Chhajlani V, Derr D, Earles B, Schmell E, August T. Purification and partial amino acid sequence analysis of human erythrocyte acetylcholinesterase. FEBS Lett. 1989 Apr 24;247(2):279-82. PMID:2714437
  2. ↑ Velan B, Grosfeld H, Kronman C, Leitner M, Gozes Y, Lazar A, Flashner Y, Marcus D, Cohen S, Shafferman A. The effect of elimination of intersubunit disulfide bonds on the activity, assembly, and secretion of recombinant human acetylcholinesterase. Expression of acetylcholinesterase Cys-580----Ala mutant. J Biol Chem. 1991 Dec 15;266(35):23977-84. PMID:1748670
  3. ↑ Shafferman A, Kronman C, Flashner Y, Leitner M, Grosfeld H, Ordentlich A, Gozes Y, Cohen S, Ariel N, Barak D, et al.. Mutagenesis of human acetylcholinesterase. Identification of residues involved in catalytic activity and in polypeptide folding. J Biol Chem. 1992 Sep 5;267(25):17640-8. PMID:1517212
  4. ↑ Yang L, He HY, Zhang XJ. Increased expression of intranuclear AChE involved in apoptosis of SK-N-SH cells. Neurosci Res. 2002 Apr;42(4):261-8. PMID:11985878
  5. ↑ Gerlits O, Fajer M, Cheng X, Blumenthal DK, Radic Z, Kovalevsky A. Structural and dynamic effects of paraoxon binding to human acetylcholinesterase by X-ray crystallography and inelastic neutron scattering. Structure. 2022 Oct 12. pii: S0969-2126(22)00373-2. doi:, 10.1016/j.str.2022.09.006. PMID:36265484 doi:http://dx.doi.org/10.1016/j.str.2022.09.006

Contents


PDB ID 8dt5

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