5fkj
From Proteopedia
Crystal structure of mouse acetylcholinesterase in complex with C-547, an alkyl ammonium derivative of 6-methyl uracil
Structural highlights
Function[ACES_MOUSE] Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Publication Abstract from PubMedInhibition of human AChE (acetylcholinesterase) and BChE (butyrylcholinesterase) by an alkylammonium derivative of 6-methyluracil, C-547, a potential drug for the treatment of MG (myasthenia gravis) was studied. Kinetic analysis of AChE inhibition showed that C-547 is a slow-binding inhibitor of type B, i.e. after formation of the initial enzyme.inhibitor complex (Ki=140 pM), an induced-fit step allows establishment of the final complex (Ki*=22 pM). The estimated koff is low, 0.05 min(-1) On the other hand, reversible inhibition of human BChE is a fast-binding process of mixed-type (Ki=1.77 muM; Ki'=3.17 muM). The crystal structure of mouse AChE complexed with C-547 was solved at 3.13 A resolution. The complex is stabilized by cation-pi, stacking and hydrogen-bonding interactions. Molecular dynamics simulations of the binding/dissociation processes of C-547 and C-35 (a non-charged analogue) to mouse and human AChEs were performed. Molecular modelling on mouse and human AChE showed that the slow step results from an enzyme conformational change that allows C-547 to cross the bottleneck in the active-site gorge, followed by formation of tight complex, as observed in the crystal structure. In contrast, the related non-charged compound C-35 is not a slow-binding inhibitor. It does not cross the bottleneck because it is not sensitive to the electrostatic driving force to reach the bottom of the gorge. Thus C-547 is one of the most potent and selective reversible inhibitors of AChE with a long residence time, tau=20 min, longer than for other reversible inhibitors used in the treatment of MG. This makes C-547 a promising drug for the treatment of this disease. Slow-binding inhibition of acetylcholinesterase by an alkylammonium derivative of 6-methyluracil: mechanism and possible advantages for myasthenia gravis treatment.,Kharlamova AD, Lushchekina SV, Petrov KA, Kots ED, Nachon F, Villard-Wandhammer M, Zueva IV, Krejci E, Reznik VS, Zobov VV, Nikolsky EE, Masson P Biochem J. 2016 May 1;473(9):1225-36. doi: 10.1042/BCJ20160084. Epub 2016 Feb 29. PMID:26929400[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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