The Active Site of a Zinc-Dependent Metalloproteinase Influences the Computed p<i>K</i><sub>a</sub> of Ligands Coordinated to the Catalytic Zinc Ion
2002-08-17T00:00:00Z (GMT) by
TNF-α converting enzyme (TACE) is a multidomain, membrane-anchored protein that includes a Zn-dependent protease domain. It releases the soluble form of cytokine tumor necrosis factor-α (TNF-α) from its membrane-bound precursor. TACE is a metalloprotease containing a catalytic glutamic acid, Glu-406, and a Zn<sup>2+</sup> ion ligated to three imidazoles. The protonation states of the active site glutamic acid and inhibitors are important factors in understanding the potency of inhibitors with acidic zinc-ligating groups such as hydroxamic and carboxylic acids. Density functional methods were utilized to compute p<i>K</i><sub>a</sub> values using a model of the catalytic site of TACE and to predict a concomitant mechanism of binding, consistent with lowering the p<i>K</i><sub>a</sub> of the bound ligand and raising the p<i>K</i><sub>a</sub> of the active site Glu-406. Weak acids, such as hydroxamic acids, bind in their neutral form and then transfer an acidic proton to Glu-406. Stronger acids, such as carboxylic acids, bind in their anionic form and require preprotonation of Glu-406. Similar binding events would be expected for other zinc-dependent proteases.
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