The structural basis for pseudoreversion of the H95N lesion by the secondary S96P mutation in triosephosphate isomerase

Biochemistry
E A KomivesD Ringe

Abstract

The structural basis for the 3000-fold decrease in catalytic efficiency of the H95N mutant chicken triosephosphate isomerase and the 60-fold regain of catalytic efficiency in the double mutant, H95N.S96P, have been analyzed. The results from a combination of X-ray crystallography and Fourier transform infrared spectroscopy experiments indicate that the predominant defect in the H95N mutant isomerase appears to be its inability to bind the substrate in a coplanar, cis conformation. The structures of each mutant isomerase were determined from X-ray crystallography of the complex of phosphoglycolohydroxamate (PGH), an intermediate analog with the isomerase, and each was solved to a resolution of 1.9 A. The PGH appeared to be in two different conformations in which the enediol-mimicking atoms, O2-N2-C1-O1, of the PGH were not coplanar. No density was observed that would correspond to the coplanar conformation. Two bands are observed for the dihydroxyacetone phosphate carbonyl in the H95N mutant FTIR spectrum, and these can be explained if the O1 of DHAP, like the O1 of PGH in the crystal structure, is in two different positions. Two ordered water molecules are located between O1 of PGH and N delta of N95. Comparison of the structur...Continue Reading

Citations

Mar 31, 2005·Annual Review of Physical Chemistry·Richard A Friesner, Victor Guallar
Jan 2, 2003·Proceedings of the National Academy of Sciences of the United States of America·Gerwald JoglLiang Tong
Feb 9, 2007·Proceedings of the National Academy of Sciences of the United States of America·Sharon Rozovsky, Ann E McDermott
Mar 6, 2004·Journal of Molecular Biology·Victor GuallarRichard A Friesner
Mar 15, 2015·Protein Engineering, Design & Selection : PEDS·Mirja KrauseRik K Wierenga
Oct 11, 2017·The Journal of Physical Chemistry. B·Hua DengRobert Callender
Apr 24, 2019·The Journal of Physical Chemistry. B·Hua DengRobert Callender

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