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6t9p

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Human Butyrylcholinesterase in complex with 2-(N-hydroxyimino)-N-[(1R)-3-{4-[(2-methyl-1H-imidazol-1-yl)methyl]-1H-1,2,3-triazol-1-yl}-1- phenylpropyl]acetamide

Structural highlights

Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.7Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Publication Abstract from PubMed

The enantiomers of racemic 2-hydroxyimino-N-(azidophenylpropyl)acetamide-derived triple-binding oxime reactivators were separated, and tested for inhibition and reactivation of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibited with tabun (GA), cyclosarin (GF), sarin (GB), and VX. Both enzymes showed the greatest affinity toward the methylimidazole derivative (III) of 2-hydroxyimino-N-(azidophenylpropyl)acetamide (I). The crystal structure was determined for the complex of oxime III within human BChE, confirming that all three binding groups interacted with active site residues. In the case of BChE inhibited by GF, oximes I (kr = 207 M-1 min-1) and III (kr = 213 M-1 min-1) showed better reactivation efficiency than the reference oxime 2-PAM. Finally, the key mechanistic steps in the reactivation of GF-inhibited BChE with oxime III were modelled using the PM7R6 method, stressing the importance of proton transfer from Nepsilon of His438 to Ogamma of Ser203 for achieving successful reactivation.

Enantioseparation, in vitro testing, and structural characterization of triple-binding reactivators of organophosphate-inhibited cholinesterases.,Marakovic N, Knezevic A, Roncevic I, Brazzolotto X, Kovarik Z, Sinko G Biochem J. 2020 Jul 8. pii: 225725. doi: 10.1042/BCJ20200192. PMID:32639532^[1]

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

References

↑ Marakovic N, Knezevic A, Roncevic I, Brazzolotto X, Kovarik Z, Sinko G. Enantioseparation, in vitro testing, and structural characterization of triple-binding reactivators of organophosphate-inhibited cholinesterases. Biochem J. 2020 Jul 8. pii: 225725. doi: 10.1042/BCJ20200192. PMID:32639532 doi:http://dx.doi.org/10.1042/BCJ20200192