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Protein Engineering vol. 9 no. 8 pp. 663-670, 1996
© 1996 Oxford University Press

RESEARCH-ARTICLE

Relationship between thermal stability and 3-D structure in a homology model of 3-isopropylmalate dehydrogenase from Escherichia coli

Csaba Magyar, András Szilágyi and Péter Závodszky1

Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences Pf. 7, H-1518 Budapest, Hungary

1To whom correspondence should be addressed

To reveal the structural basis of the increased thermal stability of 3-isopropylmalate dehydrogenase (IPMDH) from Thermus thermophilus, an extreme thermophile, the homology-based structural model of one mesophilic (Escherichia coli) counterpart, was constructed. Both IPMDHs are homodimeric proteins. We built a model of one subunit using the 3-D structures of the Th.thermophilus IPMDH and the homologous E.coli isocitrate dehydrogenase. Energy minimization and molecular dynamics simulated annealing were performed on the dimer, including a surrounding solvation shell. No serious errors were detected in the refined model using the 3-D profile method. The resulting structure was scrutinized and compared with the structure of the Th.thermophilus IPMDH. Significant differences were found in the non-specific interactions including the hydrophobic effect. The model predicts a higher number of ion pairs in the Th.thermophilus than hi the E.coli enzyme. An increase was observed in the stabilities of {alpha}-helical regions hi the thermophilic protein. The preliminary X-ray coordinates of the E.coli IPMDH were received after the completion of this work, allowing an assessment of the model in terms of the X-ray structure. The comparison proved that most of the structural features underlying the stability differences between the two enzymes were predicted correctly.

Keywords: homology modeling/3-isopropylmalate dehydrogenase/protein structure prediction/thermophiles/thermostability

Received December 8, 1995; revised March 5, 1996; accepted March 20, 1996.


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P. Zavodszky, J. Kardos, A. Svingor, and G. A. Petsko
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