2xud

Crystal structure of the Y337A mutant of mouse acetylcholinesteraseCrystal structure of the Y337A mutant of mouse acetylcholinesterase

Structural highlights 2xud is a 2 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: , , Related: 2jgh, 2whq, 1mah, 2ha6, 1maa, 2c0q, 2jgg, 2jgl, 2xug, 1q84, 2jgm, 2xuj, 2jge, 1q83, 2wls, 2xup, 2xuk, 1c2b, 2ha3, 2ha0, 2xuf, 2wu3, 2jey, 2jgi, 1n5r, 2xuh, 2jgj, 1j06, 2c0p, 2jf0, 2xuo, 2h9y, 2whr, 2xui, 1n5m, 2ha5, 2ha2, 2xuq, 2whp, 2jez, 2jgk, 1ku6, 2ha4, 1j07, 2jgf, 2ha7, 2wu4, 1c2o Activity: Acetylcholinesterase, with EC number 3.1.1.7 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [ACES_MOUSE] Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Publication Abstract from PubMed 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 2.55-2.75A 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. Conformational Remodeling of Femtomolar Inhibitor-Acetylcholinesterase Complexes in the Crystalline State.,Bourne Y, Radic Z, Taylor P, Marchot P J Am Chem Soc. 2010 Nov 19. PMID:21090615 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Acetylcholinesterase 3D structures

spinqualitylabelsall models 2xud, resolution 2.65Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image