The Active Site of a Zinc-Dependent Metalloproteinase Influences the Computed pKa of Ligands Coordinated to the Catalytic Zinc Ion
journal contributionposted on 17.08.2002 by Jason B. Cross, José S. Duca, James J. Kaminski, Vincent S. Madison
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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 Zn2+ 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 pKa values using a model of the catalytic site of TACE and to predict a concomitant mechanism of binding, consistent with lowering the pKa of the bound ligand and raising the pKa 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.