2WHQ

Crystal structure of acetylcholinesterase, phosphonylated by sarin (aged) in complex with HI-6

Summary for 2WHQ

• Entry DOI: 10.2210/pdb2whq/pdb
• Related: 1C2B 1C2O 1J06 1J07 1KU6 1MAA 1MAH 1N5M 1N5R 1Q83 1Q84 2C0P 2C0Q 2H9Y 2HA0 2HA2 2HA3 2HA4 2HA5 2HA6 2HA7 2JEY 2JEZ 2JF0 2JGE 2JGF 2JGG 2JGH 2JGI 2JGJ 2JGK 2JGL 2JGM 2WHP 2WHR
• Descriptor: ACETYLCHOLINESTERASE, 2-acetamido-2-deoxy-beta-D-glucopyranose, 4-(AMINOCARBONYL)-1-[({2-[(E)-(HYDROXYIMINO)METHYL]PYRIDINIUM-1-YL}METHOXY)METHYL]PYRIDINIUM, ... (7 entities in total)
• Functional Keywords: hi-6, synapse, membrane, secreted, hydrolase, neurotransmitter degradation, cholinesterase, serine esterase, alternative splicing, cell junction, cell membrane, disulfide bond, aged sarin, gpi-anchor, lipoprotein, glycoprotein
• Biological source: MUS MUSCULUS (MOUSE)
• Total number of polymer chains: 2
• Total formula weight: 122853.35

Authors

Ekstrom, F.,Hornberg, A.,Artursson, E.,Hammarstrom, L.G.,Schneider, G.,Pang, Y.P. (deposition date: 2009-05-06, release date: 2009-06-30, Last modification date: 2023-12-13)

Primary citation

Ekstrom, F.,Hornberg, A.,Artursson, E.,Hammarstrom, L.G.,Schneider, G.,Pang, Y.P.
Structure of Hi-6Sarin-Acetylcholinesterase Determined by X-Ray Crystallography and Molecular Dynamics Simulation: Reactivator Mechanism and Design.
Plos One, 4:E5957-, 2009

PubMed Abstract: Organophosphonates such as isopropyl metylphosphonofluoridate (sarin) are extremely toxic as they phosphonylate the catalytic serine residue of acetylcholinesterase (AChE), an enzyme essential to humans and other species. Design of effective AChE reactivators as antidotes to various organophosphonates requires information on how the reactivators interact with the phosphonylated AChEs. However, such information has not been available hitherto because of three main challenges. First, reactivators are generally flexible in order to change from the ground state to the transition state for reactivation; this flexibility discourages determination of crystal structures of AChE in complex with effective reactivators that are intrinsically disordered. Second, reactivation occurs upon binding of a reactivator to the phosphonylated AChE. Third, the phosphorous conjugate can develop resistance to reactivation. We have identified crystallographic conditions that led to the determination of a crystal structure of the sarin(nonaged)-conjugated mouse AChE in complex with [(E)-[1-[(4-carbamoylpyridin-1-ium-1-yl)methoxymethyl]pyridin-2-ylidene]methyl]-oxoazanium dichloride (HI-6) at a resolution of 2.2 A. In this structure, the carboxyamino-pyridinium ring of HI-6 is sandwiched by Tyr124 and Trp286, however, the oxime-pyridinium ring is disordered. By combining crystallography with microsecond molecular dynamics simulation, we determined the oxime-pyridinium ring structure, which shows that the oxime group of HI-6 can form a hydrogen-bond network to the sarin isopropyl ether oxygen, and a water molecule is able to form a hydrogen bond to the catalytic histidine residue and subsequently deprotonates the oxime for reactivation. These results offer insights into the reactivation mechanism of HI-6 and design of better reactivators.

PubMed: 19536291
DOI: 10.1371/JOURNAL.PONE.0005957

Experimental method

X-RAY DIFFRACTION (2.15 Å)