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B6db references: 99435740

type Journal Article
authors Sachpatzidis, A.; Dealwis, C.; Lubetsky, J. B.; Liang, P. H.; Anderson, K. S.; Lolis, E.
title Crystallographic studies of phosphonate-based alpha-reaction transition- state analogues complexed to tryptophan synthase
journal Biochemistry
ui 99435740
year (1999)
volume 38
number 39
pages 12665-74.
keywords Crystallography, X-Ray
abstract In an effort to use a structure-based approach for the design of new herbicides, the crystal structures of complexes of tryptophan synthase with a series of phosphonate enzyme inhibitors were determined at 2.3 A or higher resolution. These inhibitors were designed to mimic the transition state formed during the alpha-reaction of the enzyme and, as expected, have affinities much greater than that of the natural substrate indole-3-glycerol phosphate or its nonhydrolyzable analogue indole propanol phosphate (IPP). These inhibitors are ortho-substituted arylthioalkylphosphonate derivatives that have an sp(3)-hybridized sulfur atom, designed to mimic the putative tetrahedral transition state at the C3 atom of the indole, and lack the C2 atom to allow for higher conformational flexibility. Overall, the inhibitors bind in a fashion similar to that of IPP. Glu-49 and Phe-212 are the two active site residues whose conformation changes upon inhibitor binding. A very short hydrogen bond between a phosphonate oxygen and the Ser-235 hydroxyl oxygen may be responsible for stabilization of the enzyme- inhibitor complexes. Implications for the mechanism of catalysis as well as directions for more potent inhibitors are discussed.
last changed 2002/11/12 16:17

B6db references