5FKJ

Crystal structure of mouse acetylcholinesterase in complex with C-547, an alkyl ammonium derivative of 6-methyl uracil

Summary for 5FKJ

• Entry DOI: 10.2210/pdb5fkj/pdb
• Descriptor: ACETYLCHOLINESTERASE, 1,3-BIS[5(DIETHYL-O-NITROBENZYLAMMONIUM)PENTYL]-6-METHYLURACIL, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: hydrolase, acetylcholinesterase, c-547
• Biological source: MUS MUSCULUS (HOUSE MOUSE)
• Total number of polymer chains: 4
• Total formula weight: 244389.58

Authors

Nachon, F.,Villard-Wandhammer, M.,Petrov, K.,Masson, P. (deposition date: 2015-10-16, release date: 2016-03-16, Last modification date: 2024-01-10)

Primary citation

Kharlamova, A.D.,Lushchekina, S.V.,Petrov, K.A.,Kots, E.D.,Nachon, F.V.,Villard-Wandhammer, M.,Zueva, I.V.,Krejci, E.,Reznik, V.S.,Zobov, V.V.,Nikolsky, E.E.,Masson, P.
Slow-Binding Inhibition of Acetylcholinesterase by a 6-Methyluracil Alkyl-Ammonium Derivative: Mechanism and Advantages for Myasthenia Gravis Treatment.
Biochem.J., 473:1225-, 2016

PubMed Abstract: Inhibition 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 μM; Ki'=3.17 μM). The crystal structure of mouse AChE complexed with C-547 was solved at 3.13 Å resolution. The complex is stabilized by cation-π, 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, τ=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.

PubMed: 26929400
DOI: 10.1042/BCJ20160084

Experimental method

X-RAY DIFFRACTION (3.133 Å)