5BWC

ACETYLCHOLINESTERASE (E.C. 3.1.1.7) FROM TORPEDO CALIFORNICA IN COMPLEX WITH THE BIS-PYRIDINIUM OXIME ORTHO-7

Summary for 5BWC

• Entry DOI: 10.2210/pdb5bwc/pdb
• Related: 5BWB
• Descriptor: Acetylcholinesterase, 2-acetamido-2-deoxy-beta-D-glucopyranose, 1,7-HEPTYLENE-BIS-N,N'-SYN-2-PYRIDINIUMALDOXIME, ... (4 entities in total)
• Functional Keywords: acetylcholinesterase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Torpedo californica (Pacific electric ray)
• Total number of polymer chains: 1
• Total formula weight: 61521.37

Authors

Legler, P.M.,Millard, C.B. (deposition date: 2015-06-07, release date: 2015-09-09, Last modification date: 2024-10-23)

Primary citation

Legler, P.M.,Soojhawon, I.,Millard, C.B.
A conformational change in the peripheral anionic site of Torpedo californica acetylcholinesterase induced by a bis-imidazolium oxime.
Acta Crystallogr.,Sect.D, 71:1788-1798, 2015

PubMed Abstract: As part of ongoing efforts to design improved nerve agent antidotes, two X-ray crystal structures of Torpedo californica acetylcholinesterase (TcAChE) bound to the bis-pyridinium oxime, Ortho-7, or its experimental bis-imidazolium analogue, 2BIM-7, were determined. Bis-oximes contain two oxime groups connected by a hydrophobic linker. One oxime group of Ortho-7 binds at the entrance to the active-site gorge near Trp279, and the second binds at the bottom near Trp84 and Phe330. In the Ortho-7-TcAChE complex the oxime at the bottom of the gorge was directed towards the nucleophilic Ser200. In contrast, the oxime group of 2BIM-7 was rotated away from Ser200 and the oxime at the entrance induced a significant conformational change in the peripheral anionic site (PAS) residue Trp279. The conformational change alters the surface of the PAS and positions the imidazolium oxime of 2BIM-7 further from Ser200. The relatively weaker binding and poorer reactivation of VX-inhibited, tabun-inhibited or sarin-inhibited human acetylcholinesterase by 2BIM-7 compared with Ortho-7 may in part be owing to the unproductively bound states caught in crystallo. Overall, the reactivation efficiency of 2BIM-7 was comparable to that of 2-pyridine aldoxime methyl chloride (2-PAM), but unlike 2-PAM the bis-imidazolium oxime lacks a fixed charge, which may affect its membrane permeability.

PubMed: 26327369
DOI: 10.1107/S1399004715011281

Experimental method

X-RAY DIFFRACTION (2.45 Å)