Structural highlights
Function
[ACES_BUNFA] In muscle, it terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. In liver, its function is unclear: it could serve as a safeguard against any diffusion of acetylcholine from synapses into the circulation. In venom, its toxic role is unclear: It could result in less musculatory control by rapidly hydrolyzing acetylcholine, or that it works synergistically with alkaline phosphatase (ALP) in paralyzing prey through hypotension.
Publication Abstract from PubMed
The acetylcholinesterase found in the venom of Bungarus fasciatus (BfAChE) is produced as a soluble, non-amphiphilic monomer with a canonical catalytic domain but a distinct C-terminus compared to the other vertebrate enzymes. Moreover, the peripheral anionic site of BfAChE, a surface site located at the active-site gorge entrance, bears two substitutions altering sensitivity to cationic inhibitors. Antibody Elec410, generated against Electrophorus electricus acetylcholinesterase (EeAChE), inhibits EeAChE and BfAChE by binding to their peripheral sites. Yet both complexes retain significant residual catalytic activity, suggesting incomplete gorge occlusion by bound antibody and/or high-frequency backdoor opening. To explore a novel acetylcholinesterase species, ascertain the molecular bases of inhibition by Elec410, and document the determinants and mechanisms for backdoor opening, we solved a 2.7A-resolution crystal structure of natural BfAChE in complex with antibody fragment Fab410. Crystalline BfAChE forms the canonical dimer found in all acetylcholinesterase structures. Equally represented open and closed states of a backdoor channel, associated with alternate positions of a tyrosine phenol ring at the active site base, coexist in each subunit. At the BfAChE molecular surface, Fab410 is seated on the long Omega-loop between two N-glycan chains and partially occludes the gorge entrance, a position that fully reflects the available mutagenesis and biochemical data. Experimentally based flexible molecular docking supports a similar Fab410 binding mode onto the EeAChE antigen. These data document the molecular and dynamic peculiarities of BfAChE with high-frequency backdoor opening, and the mode of action of Elec410 as one of the largest peptidic inhibitors targeting the acetylcholinesterase peripheral site.
Crystal Structure of Snake Venom Acetylcholinesterase in Complex with Inhibitory Antibody Fragment Fab410 bound at the Peripheral Site: Evidence for Open and Closed States of a Backdoor Channel.,Bourne Y, Renault L, Marchot P J Biol Chem. 2014 Nov 19. pii: jbc.M114.603902. PMID:25411244[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Bourne Y, Renault L, Marchot P. Crystal Structure of Snake Venom Acetylcholinesterase in Complex with Inhibitory Antibody Fragment Fab410 bound at the Peripheral Site: Evidence for Open and Closed States of a Backdoor Channel. J Biol Chem. 2014 Nov 19. pii: jbc.M114.603902. PMID:25411244 doi:https://dx.doi.org/10.1074/jbc.M114.603902
