Discrimination of cognate and noncognate substrates at the active site of class II lysyl-tRNA synthetase

Biochemistry
Sandro F Ataide, Michael Ibba

Abstract

Within the two unrelated aminoacyl-tRNA synthetase classes, lysyl-tRNA synthetase (LysRS) is the only example known to exist in both classes. To probe the role of the amino acids responsible for L-lysine binding in the active site of the class II LysRS (LysRS2), we studied the lysS-encoded Escherichia coli protein. On the basis of the structure of L-lysine complexed with E. coli LysRS2 (lysS), residues implicated in amino acid recognition and discrimination were systematically replaced. Steady-state kinetic parameters for these variants showed reductions in the catalytic efficiency (k(cat)/K(M)) of 1-3 orders of magnitude, allowing the assignment of specific roles for key residues in the active site of LysRS2. To further investigate the role of each residue in discrimination against noncognate amino acids, steady-state kinetic parameters were determined for the nonprotein amino acid S-(2-aminoethyl)-L-cysteine, a potent inhibitor of LysRS2. While a number of variants showed reductions of several hundred-fold in efficiency of S-(2-aminoethyl)-L-cysteine utilization, this was uniformly accompanied by similar reductions in the efficiency of lysine utilization. Thus, manipulation of the amino acid binding site only allowed up to a ...Continue Reading

References

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Citations

Oct 1, 1993·European Journal of Pediatrics·U Blecker, Y Vandenplas
Dec 25, 2007·ACS Chemical Biology·Sandro F AtaideMichael Ibba
Sep 8, 2009·The Journal of Biological Chemistry·Hervé Roy, Michael Ibba
Aug 16, 2011·Nature Chemical Biology·Hervé RoyMichael Ibba
Apr 28, 2007·Expert Opinion on Investigational Drugs·Urs A OchsnerNebojsa Janjic
Jun 29, 2010·FEBS Letters·Alexandre AmbrogellySarath Moses
Feb 5, 2008·Methods : a Companion to Methods in Enzymology·Hervé Roy, Michael Ibba
Aug 11, 2007·The Journal of Biological Chemistry·Damien ThompsonThomas Simonson
Aug 26, 2014·Molecular Systems Biology·Matthew ScottTerence Hwa
Apr 23, 2008·Journal of Combinatorial Chemistry·Josep Farrera-SinfreuMiriam Royo
Dec 14, 2006·ACS Chemical Biology·Sandro F Ataide, Michael Ibba

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