Crystallographic snapshots of nonaged and aged conjugates of soman with acetylcholinesterase, and of a ternary complex of the aged conjugate with pralidoxime

J Med Chem. 2009 Dec 10;52(23):7593-603. doi: 10.1021/jm900433t.


Organophosphate compounds (OP) are potent inhibitors of acetylcholinesterases (AChEs) and can cause lethal poisoning in humans. Inhibition of AChEs by the OP soman involves phosphonylation of the catalytic serine, and subsequent dealkylation produces a form known as the "aged" enzyme. The nonaged form can be reactivated to a certain extent by nucleophiles, such as pralidoxime (2-PAM), whereas aged forms of OP-inhibited AChEs are totally resistant to reactivation. Here, we solved the X-ray crystal structures of AChE from Torpedo californica (TcAChE) conjugated with soman before and after aging. The absolute configuration of the soman stereoisomer adduct in the nonaged conjugate is P(S)C(R). A structural reorientation of the catalytic His440 side chain was observed during the aging process. Furthermore, the crystal structure of the ternary complex of the aged conjugate with 2-PAM revealed that the orientation of the oxime function does not permit nucleophilic attack on the phosphorus atom, thus providing a plausible explanation for its failure to reactivate the aged soman/AChE conjugate. Together, these three crystal structures provide an experimental basis for the design of new reactivators.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry*
  • Acetylcholinesterase / metabolism*
  • Animals
  • Catalytic Domain
  • Cholinesterase Inhibitors / chemistry*
  • Cholinesterase Inhibitors / metabolism*
  • Cholinesterase Inhibitors / pharmacology
  • Crystallography, X-Ray
  • Dealkylation
  • Enzyme Activation / drug effects
  • Humans
  • Kinetics
  • Models, Molecular
  • Pralidoxime Compounds / chemistry*
  • Pralidoxime Compounds / pharmacology
  • Soman / chemistry*
  • Soman / metabolism*
  • Soman / pharmacology
  • Torpedo
  • Water / chemistry
  • Water / metabolism


  • Cholinesterase Inhibitors
  • Pralidoxime Compounds
  • Water
  • Soman
  • Acetylcholinesterase
  • pralidoxime