The Role of Strong Electrostatic Interactions at the Dimer Interface of Human Glutathione Synthetase |
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Authors: | Margarita C. De Jesus Brandall L. Ingle Khaldoon A. Barakat Bisesh Shrestha Kerri D. Slavens Thomas R. Cundari Mary E. Anderson |
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Affiliation: | 1. Department of Chemistry and Biochemistry, Texas Woman’s University, P.O. Box 425859, Denton, TX, 76204, USA 2. Center for Advanced Scientific Computing and Modeling (CASCaM), Department of Chemistry, University of North Texas, Denton, TX, 76203, USA
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Abstract: | The obligate homodimer human glutathione synthetase (hGS) provides an ideal system for exploring the role of protein–protein interactions in the structural stability, activity and allostery of enzymes. The two active sites of hGS, which are 40 Å apart, display allosteric modulation by the substrate γ-glutamylcysteine (γ-GC) during the synthesis of glutathione, a key cellular antioxidant. The two subunits interact at a relatively small dimer interface dominated by electrostatic interactions between S42, R221, and D24. Alanine scans of these sites result in enzymes with decreased activity, altered γ-GC affinity, and decreased thermal stability. Molecular dynamics simulations indicate these mutations disrupt interchain bonding and impact the tertiary structure of hGS. While the ionic hydrogen bonds and salt bridges between S42, R221, and D24 do not mediate allosteric communication in hGS, these interactions have a dramatic impact on the activity and structural stability of the enzyme. |
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