Monomethylarsenite Competes with Zn2+ for Binding Sites in the Glucocorticoid Receptor

Abstract

The binding of arsenite (As(III)) and monomethylarsenite (MMAIII) to the DNA-binding domain of the glucocorticoid receptor (GR-DBD) and their competition with the two required Zn2+ ions of this domain have been investigated with isothermal titration calorimetry (ITC) and circular dichroism (CD). The binding thermodynamics indicate that MMAIII, but not arsenite, is able to compete with one of the two Zn2+ ions. This has been confirmed by monitoring arsenite and MMAIII titrations of Zn2GR-DBD with CD. Only MMAIII is able to eliminate the Zn-stabilized secondary structure, consistent with partial or complete displacement of at least one Zn2+ ion and, therefore, loss of GR-DBD competence to bind to the DNA of its recognition site, the glucocorticoid response element (GRE).