Bourne_2010_J.Am.Chem.Soc_132_18292

Reference

Title : Conformational remodeling of femtomolar inhibitor-acetylcholinesterase complexes in the crystalline state - Bourne_2010_J.Am.Chem.Soc_132_18292
Author(s) : Bourne Y , Radic Z , Taylor P , Marchot P
Ref : Journal of the American Chemical Society , 132 :18292 , 2010
Abstract :

The active center of acetylcholinesterase (AChE), a target site for competitive inhibitors, resides centrosymmetric to the subunit at the base of a deep, narrow gorge lined by aromatic residues. At the gorge entry, a peripheral site encompasses overlapping binding loci for noncompetitive inhibitors, which alter substrate access to the gorge. The click-chemistry inhibitor TZ2PA6 links the active center ligand, tacrine, to the peripheral site ligand, propidium, through a biorthogonal reaction of an acetylene and an azide that forms either a syn1 or an anti1 triazole. Compared with wild-type mouse AChE, a Tyr337Ala mutant displays full catalytic activity, albeit with 2-3 orders of magnitude higher affinities for the TZ2PA6 syn1 and anti1 regioisomers, reflected in low femtomolar K(d) values, diffusion-limited association, and dissociation half-times greater than 1 month and 1 week, respectively. Three structures of each of the co-crystallized syn1 and anti1 complexes of the Tyr337Ala mutant were solved at three distinct times of crystal maturation, consistent with or exceeding the half-lives of the complexes in solution, while crystalline complexes obtained from soaked Tyr337Ala crystals led to picturing "freshly formed" complexes. The structures, at 2.55-2.75 A resolution, reveal a range of unprecedented conformations of the bound regioisomers, not observed in the wild-type AChE complexes, associated with concerted positional rearrangements of side chains in the enzyme gorge. Moreover, time-dependent conformational remodeling of the crystalline complexes appears to correlate with the dissociation half-times of the solution complexes. Hence, for the tight-binding TZ2PA6 inhibitors, the initial complexes kinetically driven in solution slowly form more stable complexes governed by thermodynamic equilibrium and observable in mature crystals.

PubMedSearch : Bourne_2010_J.Am.Chem.Soc_132_18292
PubMedID: 21090615
Gene_locus related to this paper: mouse-ACHE

Related information

Mutation Y337A_mouse-ACHE
Inhibitor Y337A_mouse-ACHE    Tz2Pa6-syn1    Tz2Pa6-anti1
Gene_locus Y337A_mouse-ACHE    Tz2Pa6-syn1    Tz2Pa6-anti1    mouse-ACHE
Structure Y337A_mouse-ACHE    Tz2Pa6-syn1    Tz2Pa6-anti1    mouse-ACHE    2XUF    2XUG    2XUH    2XUI    2XUJ    2XUK    2XUO    2XUP    2XUQ    2XUD

Citations formats

Bourne Y, Radic Z, Taylor P, Marchot P (2010)
Conformational remodeling of femtomolar inhibitor-acetylcholinesterase complexes in the crystalline state
Journal of the American Chemical Society 132 :18292

Bourne Y, Radic Z, Taylor P, Marchot P (2010)
Journal of the American Chemical Society 132 :18292