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  • Title: Physical basis of structural and catalytic Zn-binding sites in proteins.
    Author: Lee YM, Lim C.
    Journal: J Mol Biol; 2008 Jun 06; 379(3):545-53. PubMed ID: 18462757.
    Abstract:
    Zn(2+), an element that is essential to all life forms, can play a catalytic or a solely structural role. Previous works have shown that Zn(2+) binds preferentially to water molecules and His in catalytic sites, but to Cys(-) instructural sites, but the molecular basis for the observed ligand preference is unclear. Here, we show that the different Zn(2+) roles are also reflected in the different bond distances to Zn(2+) in structural and catalytic sites. We reveal the physical basis for the observed differences between structural and catalytic Zn sites: In most catalytic sites, water is found bound to Zn(2+) as it transfers the least charge to Zn(2+) and is less bulky compared to the protein ligands, enabling Zn(2+) to serve as a Lewis acid in catalysis. In most structural sites, however, >/= 2 Cys(-) are found bound to Zn(2+), as Cys(-) transfers the most charge to Zn(2+) and reduces the Zn charge to such an extent that Zn(2+) can no longer act as a Lewis acid; furthermore, steric repulsion among the bulky Cys(S(-)) prevents Zn(2+) from accommodating another ligand. Based on the observed ligand preference and Zn-ligand distance differences between structural and catalytic Zn sites, we present a simple method for distinguishing the two types of sites and for verifying the catalytic role of Zn(2+). Finally, we discuss how the physical bases revealed aid in designing potential drug molecules that target Zn proteins.
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